Great. Good morning. Welcome, everyone. I'm Jessica Fye, a biotech analyst at J.P. Morgan. We're so excited to be starting the 44th Annual J.P. Morgan Healthcare Conference this week with Ascendis. The company's CEO, Jan Mikkelsen, is going to give a presentation. That's going to be followed by some Q&A. But first, it looks like I'm passing it on to Scott Smith, the CFO, for a forward-looking statement.
Thanks a lot, Jess. It's my honor to read the first FLS of the year for Ascendis Pharma. Before we begin, I would like to remind you that this conference call will contain forward-looking statements that are intended to be covered under the safe harbor provided by the Private Securities Litigation Reform Act. Examples of such statements may include, but are not limited to, statements regarding our commercialization, continued development of Skytrofa and Yorvipath, as well as certain revenue and growth expectations, our pipeline candidates and expectations with respect to their costs, continued progress, potential commercialization and success, our strategic partners, partnerships and investments, our goals regarding our clinical pipeline, including timing and results of our clinical trials, and our ongoing and planned regulatory filings and expectations regarding the timing and results of regulatory decisions. These statements are based on information that is available to us today.
Actual results could differ materially from those in our forward-looking statements, and you should not place undue reliance on these statements. We assume no obligation to update these statements as circumstances change, except as required by law. For additional information concerning the factors that could cause actual results to differ materially, please see our Forward-Looking Statements section in our press release dated January 9, 2026, and the Risk Factors section of our most recent annual report on Form 20-F filed with the SEC on February 12, 2025. With that, I'll hand it over to Jan.
Thanks, Scott. Do us the first two minutes.
It's actually with extreme proudness I'm standing up here today. It started actually in December last year because we really had a celebration. Ascendis Pharma turned out to be 18 years. At least in Denmark, it means one thing: you throw your children away, and they are financially independent. That is the key thing. You don't fund them more. That was exactly what happened at that time for Ascendis. After 18 years, we came to the States, building on our TransCon technology, building on our R&D engine, building on our late-stage clinical development, building on what we call the last stage of the rocket, how really to do global commercialization. We came to the States where we had two quarters of a profitable business. I call it going over the black hole because so few companies managed to come to that.
So when you think about Ascendis, we're basically on the edge of growing up. We're on the edge really to become a leading biopharma company. Looking on the number, Q4 product revenue, about EUR 240 million, with the entire year of about EUR 683 million. And Scott, which is really strong in numbers, he can calculate that it really impacts a major increase in the year of 2025, and that will continue. This revenue base is built mainly on two products, Yorvipath and Skytrofa. This is like having two bullets being fired, and you already see the benefit on it. And now the last bullet is coming, where we basically have our PDUFA date for TransCon CNP here in February. But we're not stopping there because I think this is the key thing with Ascendis Pharma.
We got built on a strong technology platform, the TransCon technology, and we will sustain leadership to new product development, LCM activity, and other patient offerings we can do. But we're also creating value outside where we're known from, our rare disease. We have in ophthalmology our spin-off company, Eyconis, in obesity and metabolic. We are working with Novo Nordisk. And in oncology, we have our own internal development. I will come back to some of this later on. But I always like to take the vision up because this is our guiding principle: where do we really want to come? And it gives us really the strategic roadmap for the next years until 2030. And you can see we basically have changed one single bullet.
It's the first bullet because we're now feeling confident that we can take and have a revenue of more than EUR 5 billion in 2030.
It will be a global revenue where we're aiming for having a split between U.S. and ex-U.S., where we believe the majority will come from the U.S., but there will be a major, major contribution from ex-U.S. We will be the leader in growth disorder and hypopara. We're already there, but we will continue it to an investment in new chemical entities, in our LCM activities, and other elements in it. And as Kennett will explain later on, we're now expanding our rare disease endocrine pipeline with two to three product opportunities. Don't forget, through the TransCon technology, we are in a unique position. The way we use our algorithm is that we basically have got basically now expect to get three out of three, start with three preclinical candidates, and get three products to approval. And they're highly differentiated, and no one ever can really repeat and make them.
And I think that is the value you see in Ascendis Pharma. This is sustainability with durability because of our IP and other things. And also, this is combination product. We will still go through our areas of business model where we're still investing in other areas outside rare disease endocrinology, for example, in obesity with our collaboration with Novo Nordisk in ophthalmology, where we really see the applicability of the TransCon technology, also making a highly differentiated product. But we will always be working on the fundamentals for us. Outperform industry drug development benchmark, try to be extremely successful, and really live up to our values, the patient, the science, and the passion. So this is what everything we're doing is built on. And that is a technology platform expanding year by year. We see it being expanded again.
Now the latest one is the protein degraders, where we basically can take hormones, other things away from the body in a continued manner. This is our late-stage pipeline. This is our current pipeline internally only in basic from our rare disease endocrinology products. Going to our R&D platform. Today, we have two products approved. We have three indications. Two new launches, label expansion, partnership. We have an aspiration for 2035. Eight plus new chemicals approved. They're all durable, long IP, highly differentiated, plus 25 indications. And you can see the fundamentals there. There is some of the new product opportunities that are coming up, and you can also see there will be a larger indication being split into partnerships. Going to TransCon PTH, our leading product in hypopara. This is just giving you an illustration about the, you can say, the size of this market here.
In the U.S., 70-90K, which are what we call the lowest number. Some people actually believe it's 100% higher. Europe direct, 150-200. International market, a huge market. This is where we're building up a global commercialization. Currently, we see the big driver of the revenue increase has mainly been from the U.S. side. What we see by long-term basis, the ex-U.S. will take over more and more because it's much more fragmented. It takes longer time to penetrate, but you will really see the high value because of the large patient population. This is what we call the global commercial update. If you start on the U.S., we have 5,300 unique prescriptions. We have nearly 2,400 prescribers.
You can see we have a constant flow every quarter of nearly the same amount of prescription, and we see the broadening and broadening of the prescription base. Still a unique opportunity with less than 5% penetration of the drug today. In Europe direct, we only launched in three countries now: Germany, Austria, and Spain. And Spain only started in Q3. Here in 2026, we expect to have up to plus 10 countries coming in. This is where we see the big expansion of countries coming in. In Europe direct, this is where we have direct commercialization. In the international market, we only cover through named patient program, but we have distribution agreements in 75% of countries. And we're also seeing our partner, Teijin, got the approval, has been launched in Japan, which we're really looking forward to seeing how we penetrate this market segment.
Going to the right, you can see the increase in global revenue. It's pretty clear. We're really increasing and accelerating the revenue, $40-$50 million every quarter. Why I call it the building a big house? This is like building the Europe head skyscraper in Manhattan because you're basically building one or two floors every quarter, and it's getting taller and taller because patients stay on treatment. They stay on treatment. This is why we see this acceleration in revenue, which we hope we will see the same thing in 2026. Then we will see the biggest, biggest tower ever being built in Manhattan. There's been a lot of discussion about how we look at once-weekly product. We had a once-weekly product. We had also a clear way how we see the utilization of a once-weekly product.
We cannot see any other reason that every patient needs to be tried with a daily product, out from the idea that you are taking a lot of conventional therapy and at the same time you're adjusting the dose to be right for the patient. Doing that with a weekly product makes no sense. So when we see the utilization of a one-weekly product, it will basically be when we have stable patients. We believe about 35%-40% will be stable when they have been titrated to a stable level of Yorvipath. For them, we really believe it could be a benefit for them to move over on a one-weekly product.
If they then feel that they are in a position that things change for them, they need to change their life, they need to have more exercise, sure, they can go back to the one-weekly product or add in a one-day product. We developed one product, but we also know we made a benchmark with Yorvipath. If you go to some of the FDA regulatory documents, it's quite sure when there is a benchmark on a daily product, you cannot compromise safety and efficacy. We needed to develop a complete new product when we saw that and got that interaction. We said we need basically to be bioequivalent every day in the week with what we call a weekly product. That is what we developed here. If you see our data to the left, this is in monkeys.
When we do the human prediction, which we always have been 110% spot on, we never had anyone that had been different. You see the profile over once weekly, and then you compare to Yorvipath over one day. Clearly, always in the same interval, always is basically a bioequivalent. It's the same product, the same active ingredients, the same element. The only thing we're changing is the linker. This is why we really believe there can be fast condensed program and helping the patient that really wants to move over to that. When I look on our TransCon PTHs, it's now indicated in adults. We had Q4 revenue of nearly €190, and we saw a full-year revenue of €470-€480. When I see in the US, we expect to see a steady state increase in the US.
If I go to ex-US, we will see in 2026 likely an increase because we're getting more and more countries on board. We're getting more and more full commercial. We move away from named patient program. So when I see the ex-US for the next three, four, five years, you will see much more growth there in what I call an acceleration. Clinical program to expand the labeling in the US, we have our pathway 60, where we have a program to move up to 600 micrograms per day. We have our pathway going on to younger children. Now we are in the stage for 12 to 18. When we have gone through that, we will likely go down to even younger children. The once weekly, we have it. We believe in this.
This is exactly built on the TransCon technology, where we never, never have failed on a preclinical candidate. We go into our global commercialization, and we expect launches in 10 additional countries here in 2026. Think about this. This is a durable product. When I look at the competition, I see no competition. If I look on the lifespan of this product, that is a combination product. It will be there for the next 10, 20 years. This is why I don't see any way where we're now going for what we call value optimization in each country. We're not going for sprinting into the market. We're going for the value optimization. Going to Skytrofa, I really love this product. It's approved in US and other countries in a single indication, pediatric growth hormone deficiency. In this year, we expanded it to adult growth hormone deficiency in the US.
It was our first label expansion. We now have a basket trial for basically four additional indications that we are running now, so we can basically expand to all the established growth hormone indications. We are also going to a new era, combine it with, for example, TransCon CNP in achondroplasia and hypochondroplasia. What we want really to do is really make this to a growing product. How do we do it? Growing the basic business. We have strong belief that it's happening. We see the consolidation of the daily growth hormone. We see also how Skytrofa in its best-in-class properties really increasing the brand share. We expand to all the traditional growth hormone indication. We add now new novel growth hormone indication, and we broaden the geographic reach. This is how we're building this up to a blockbuster product.
Going to TransCon CNP, we designed it, TransCon CNP, to provide a sustainable exposure of CNP, of wild-type CNP in the prodrug technology to avoid any kind of injection site reaction. And this is what we saw in the peer-reviewed validation of it. Yes, we enhanced linear growth as much as ever you can get out of inhibition of the tyrosine kinase. We give for the first time benefit beyond linear growth compared to placebo in a controlled trial. There was no evidence of hypertension, low immunogenic signal. And because we used the prodrug technology, no injection site reaction and once-weekly administration. So where are we? Yes, we achieved really the target product profile. We have now durable response for up to three years in our open-label extension.
We have our PDUFA date here in end of February, and we have our EMA submission where we expect a decision in Q4. I have no doubt TransCon CNP really are providing the benefit that is needed to this patient group, really showing benefit beyond linear growth because that is the key element. But we also want to improve it further on. Can we boost the response if you have a child that has not been treated just for being newborn? And that is what we have done in our combination therapy, which I will come to next one. So the idea is this basically. When you do have achondroplasia, you have a hyperactive FGFR3 tyrosine kinase. This is basically putting a brake on the system. This is taking a car, sitting up on a hill here in San Francisco, and then you take a brake on. It's standing there.
This is what you basically see in this situation. When you increased, let the brake go, it starts rolling. Independent of how you let the brake go, if you take it electronically, you take it by hand or other thing, they're basically moving up to the same growth velocity, about 5.5-6.0 in annualized growth. Depending on gender, you can see it much easier in z-score about 0.3. This is what you get when you remove the brake. The idea is that when you remove the brake, you basically have a new opportunity to take a growth stimulation. This is where growth hormone comes in because you can really see for this scheme, if you take the green one and basically remove the brake, then you really can get the full potential of growth hormone.
So when people say growth hormone is not functioning in achondroplasia, yes, it's not functioning when you don't have the brake off. If you have the brake off, you get perhaps one centimeter in one year. I heard some people coming explain to me we're getting eight centimeter. Then I said, if we're really getting eight centimeter, then quite sure growth hormone will be utilized everywhere in the world and not only in Japan. It's pretty obvious. No one gets eight centimeter. This is make no sense. So you get about one centimeter when you really give it, and it's not really durable over three, four, five. You still get some benefit. And there was a way you can see addressing the tyrosine kinase come in. That is biology by what we are doing.
So when we see here the safety, because that is basic number one in any pediatric indication. Safety, safety, safety. The risk of exposing a child to something that can harm it, can give late-stage complication or anything like that. So when we look on this here, one of the best safety I've ever seen in this indication. So this is really the key. If any one of you look at this here, it basically say anything of this here, and it's focused on growth velocity. So if you take the gray, that is new patients, and you look on the growth curve or the growth scattering, what we call achondroplasia growth charts, you have 50%, which are a normal growth pattern of a child with achondroplasia. Then you have the 5% and 95%. This is how you can take it.
The average stature of a child is what a normal child would grow to. This is the blue one. There you can see we have the 3% and the 97%. So when we take a new patient into our combination trial, they are growing at 4.92 centimeters per year. When you go up and look, oh, they're under the 50th percentile. Oh, they're growing exactly as you expect of an achondroplasia child. When they come into the combination, they're actually growing more than you see in a normal child in a growth spurt. I have no belief that could happen. Then we say, what is happening then in the children that are already in CNP treatment for more than two years? Okay, look at them. They are starting not on the 50th percentile.
They're starting much more up on the 95th percentile for stature because they've got CNP therapy for two, three years, and therefore, they have a benefit on it, but when we give them growth hormone, they're also moving up, so independent if you have been on CNP or not on CNP, you basically can see that you basically can move the children up to a growth spurt more than you see in a normal child. If anyone has seen that more than one age, I've never seen that, and I didn't believe it basically was possible to do, so what is really happening with the growth of the child? Are everything being built in a normalization of the child? Look here on body proportionality. Never seen an improvement in body proportionality to that level before, and then something completely new.
We have never seen that to a level on monotherapy in any way, increasing the arm span. That is a key element for the comorbidity that really limits them in a lot of physical activity, the short arm. When you see that, you see the same pattern, the new patient moving up, but also the patient that has been on CNP moving up over the 94% fracture. Never seen before. First time I ever seen an improvement in an important comorbidity as arm span. There has been a lot of talk about rewinding of the signal. It's getting weaker and weaker. There haven't been discussions on that. Oh, there's negative growth in the children. I don't know so much I hear sometimes.
But when I look on this curve here and then look just to the right, TransCon CNP monotherapy, and look on the 26-week and the 52-week, and you see a small decrease, 3-4%. When you go and see on the control trial, the same decrease, 3-4%. So what is really happening is you are applying a complete new biology where the widening effect of growth hormone that has been seen in achondroplasia is not existing. And if people don't believe it, then look at the data. There is the same small decline that you see with CNP monotherapy. Really, really unique data, never seen any time before. So when I look on this program here, it's why we really are going to be the leader in growth disorder because we exceed every historical benchmark for growth without compromising safety and tolerability. This is a new benchmark.
Go out and ask anyone else, get this same effect and see if you can get it. And the safety is really as what you hope for. CNP has proven to be one of the most safe therapies for years and years in patients. Growth hormone has been the same thing. So combining two safe, well-known things in a pediatric indication, yes. 100% of the children completed it. Still on treatment. The burden of two injections a week is far out for what the element of the benefit we've seen. And the bone age remain consistent with chronological age. We had two informal meetings with FDA. We went in and started now the phase three trial. We have signed the protocol and started enrolling a patient in this Q1. We will also come up with the week 78 core data here in Q2. They're continuing now in two years.
It's an open label extension for one year more, and we initiate new trials where we're also using this company. This is the most powerful combination in the 20-plus growth disorder that exists today. Collaboration and partnership. Novo Nordisk, yes, we developed the first once-monthly product with the best profile ever seen. That's why Novo Nordisk signed the agreement with us and not other companies. And it's on track. You will see the benefit of that. It's a unique product. We formed Eyconis, where we took all our ophthalmology product in. We're moving forward. Also, they're going in clinic this year. Teijin, they have all rights in Japan, and they're executing excellently, get the first product into the market now. And VISEN is doing the same in China. Financial update.
This is typically a slide that is dedicated to Scott, but Scott gave it to me today to go through it. And when I look on our product revenue, $683 million, yes, we really are on an edge where we're moving up. When you look on the number for 2024, huge, huge, huge, huge difference. And it continues. Yorvipath is the main driver of the acceleration, 477. SKYTROFA 206, total full year, 720. And what we always said, we invested in highly profitable product. You don't pay bills with revenue. You pay bills with profit. And that is what we are also doing in SKYTROFA. We only taking really the revenue when it's highly profitable. So we even in 25 increase our profit range there. Total full year operating expenses, 762. Really control it, really take it in the way we want to do it.
Cash balance €615 million, increasing quarter by quarter now. And we expect to have an operating cash flow of at least EUR 500 million. This is the dedication and how our fundamentals are, how we can accelerate revenue at the same time we can control expenses, but not compromising our investment in globalization, not compromising our investment in life cycle market, not compromise any of our investment that's coming in further. We also plan to buy at least $120 million shares back this year because the board said to me, "Yeah, you're not a bank. You basically need to do something with your cash." So this is the R&D milestone for 2026. And you can see we expect the CNP approval here in the Q1. We will come up with a 78-week data here in Q2 from our combination trial.
As a little goody, we will come out with our overall survival in platinum position ovarian cancer, where we enrolled seven share patients. We expected it to here in Q1, but it's actually really positive when you delay OS for one quarter, in my view, because it's just meaning is that we only in the 30s. So we still have a long way to go before we can go up to the OS. TransCon CNP, complete enrollment of the achondroplasia infant trial. We then have Q4 pediatric decision of CNP, initial proof of concept study in adult. This is also where we move in. There is a lot of comorbidity in adults, and we really have a product that really can show this benefit. We will give you the two-year update from our combination trial.
We will have complete recruitment in our basket trial, and we also will have complete recruitment in our 60 trial. So thank you a lot for listening to us today. The Ascendis team is really proud. We feel we are on the edge of really being a leading biopharma company. We had all the fundamentals before with TransCon technology, our R&D engine, our commercialization. We really built it up in the last two years to be a global commercial organization. And now we see the revenue coming in. And this is where I said Ascendis Pharma, the edge to be a biopharma company. Thanks so much.
Thank you. Great. So we're going to go into Q&A here. And if you're in the room, just feel free to raise your hand or you can send me questions on the iPad up here through the portal. Yorvipath's been off to a very rapid start. How should we think about the growth drivers in the U.S. and Europe in 2026? And are there any underappreciated factors that could meaningfully influence the ramp this year?
There's two. That's divided in U.S. and ex-U.S. And I think, Jay, you would take U.S., how you really are ramping up and doing all different kind of effort to really expand and accelerate.
S ure. So I would say in the U.S., we probably have three primary focuses. One is, you saw earlier, the penetration in the U.S. is still quite low, right? So there's a lot of opportunity remaining, particularly in a rare disease condition where there's still an evolving understanding of the condition itself. So the three things specifically, I would say one is we're still engaging heavily in increasing that provider education and base, right?
So there's still ample room for us to increase not only the number of prescribers that may be prescribing something for the first time beyond conventional therapy, as well as expanding their perception of the eligible patient for hypoparathyroidism, given that some of these patients historically have just primarily been treated with conventional therapy. The second area I would say is patient activation is a big piece, right? So whenever you're looking at any kind of underpenetrated larger group of patients, really thinking about how you reach a diffuse group of patients that may not have established care, thinking about how to reach them through digital channels, that's going to be a big focus for us in 2026 as well.
Then lastly, I would say the third is we're constantly investing in just how we approach access and patient support, recognizing that experience, particularly again in these rare conditions, is incredibly important, not only because it's the right thing to do for the community, but also because it materially impacts that patient experience while being treated with Yorvipath. In ex-US, we're using some of the same strategic element for discussion in Germany, for example, the most mature country from our European launch. In the other countries, you can say it's really, really simple. Get full commercial launch, and this is where we expect to add at least 10 more countries.
In the US, I think last year was a lot of focus on kind of the time from a patient getting their prescription to when it was reimbursed. How do you see that evolving as the launch goes on?
Jay?
So I would say that a lot of the evolution in itself is time, right? So when you think about evolution, there's a difference between like, are you doing anything materially different from an activity standpoint? And I would say the team is doing the things that you would expect to do. Because the clinical value proposition is so strong for Yorvipath, it's important for us to be able to continue to tell that story. But the time lag that you see for a lot of these rolling staggered reviews for a lot of the fragmented payer system in the U.S. simply requires that time, patience, discipline, continued engagement, and education. So I don't think the strategy in and of itself will change because the value proposition is strong.
But I do anticipate that the needle will continue to move upwards that you would expect with any launch trajectory. But we actually feel really good about where we are today. And I think the % coverage and the approval rates that you're seeing so quickly out of the gates is a testament to the strong clinical value proposition that we have.
Great. We're getting a couple of audience questions in here. So for TransCon PTH, Yorvipath, given the low level of penetration in the US, can we expect quarterly new patient adds stabilize at the level you saw in the fourth quarter?
Jay?
I think what you're seeing now is steady additions of new patients. And I think next year, again, where the three areas that we talked about, we do anticipate continued growth throughout 2026. So we're optimistic that we'll see that continued growth.
I think it just we also need to look on the penetration. We're down on perhaps 3-4% of the patient population. And when we look on the clinical benefit we have provided to our clinical trial, there was no one single patient group or patient that didn't benefit on being on treatment. So in a theoretical optimized positive world, 100% of the patients should be on. Think about having type 1 diabetes without insulin. Having hypopar without PTH, for me, it's the same thing.
Some other questions coming in on the weekly PTH product. Can you elaborate on what the differences are between this weekly PTH and the MBX product? And can you talk about the registrational path for the weekly? What could that look like? Could it just be kind of PKPD bridging? Do you need a separate phase three efficacy trial?
Yeah. I will start with one and Kennett will take over. I think the key element, how we designed our once-weekly product, is to build on Yorvipath. The same mode of action, the same active ingredients, the same way of designing, just changing the linker. So we basically are taking the same benefit you've seen with Yorvipath. We expect 110% also to see with our once-weekly TransCon PTHs. About MBX, it has nothing to do with basically the benefit we see with Yorvipath or anything like that. And Kennett, you can explain the mode of action because it's a complete different design of this molecule.
Yeah. So what we wanted to do is build on the success that we have with Yorvipath and having the release of unmodified PTHs that can reach receptors in all of the target tissues.
So when we wanted to design the once-weekly, we wanted to be able to do exactly that. As Jan was mentioning in the presentation, we actually made a first-generation once-weekly PTH. This molecule actually had a peak to trough of 1.7. And by the modeling that we also showed that we're doing for this compound, we could see that would probably be too much over the course of a week. So you would have periods where patients could be hypercalcemic and times where they would be hypocalcemic over the course of a week because we have set that benchmark with Yorvipath where we have a peak to trough of 1.3. So we knew what the outer bounds for peak to trough could be. So we actually had to come up with new technology or new TransCon linkers that would address that particular point.
This is what our scientists have been able to do. And this is why you can now see over the course of a week, we had exactly the same variation in plasma exposure as you're seeing with Yorvipath. And this is why we're quite comfortable. Not comfortable.
Confident. Thank you, Anne. If I had been Jan, I would have just continued talking and nobody would have understood. Confident that we actually have the right PK profile to address the needs for patients over the course of a week. Just to sum up, Jess, Yorvipath, TransCon once-weekly TransCon PTH, it's an extremely durable product. If I look on the competitive landscape, there's nothing, nothing that's living up to the benefit we see with Yorvipath.
So this is why when I look in the next 15, 20 years, I cannot see anything that can come in and basically be in position to substitute or just living up to the standard of benefit we're giving with Yorvipath. MBX, a complete mode of action, not giving anything, what I call in replacement therapy, totally different mode of action. And the lack of data, I think, also illustrates that.
Our last 30 seconds. Can you remind me what your peak sales expectations are for Yorvipath?
In the US or global basis? About both. I think it will be at least $5-$8 billion just for that product.
Worldwide?
Yes. But typically, I'm wrong because I'm very conservative from the countryside. So likely it will be higher. Great. Thank you. Thanks a lot, Jess.
Good morning. Thanks for joining us for another session at the 44th J.P. Morgan Healthcare Conference. I'm Brian Cheng. I'm one of the senior biotech analysts here at the firm. On stage, we have Sam from CRISPR Therapeutics. I'll now pass the mic to their CEO, Sam, for a short presentation followed by a live audience Q&A. Sam, the stage is yours. Thank you.
Good morning, everyone. Thank you, Brian, for the introduction. We're very pleased to be here today to present the progress and updates for CRISPR Therapeutics. Before I jump in, here are FLS statements. We're nearly a decade into our mission of transforming medicine with gene editing by developing cures for patients with serious diseases, and today, we're very happy to be in a very strong position with progress across four franchises.
With HEME, we have an approved product on the market today together with our partners, Vertex and Casgevy, which has multi-billion-dollar revenue potential. We continue to expand the addressable population that Casgevy can address. And we have efforts ongoing for in vivo gene editing that can significantly improve access for patients suffering from sickle cell disease. Beyond that, we have a tremendous focus on our in vivo platform where we're doing in vivo gene editing of the liver. We published transformative data for CTX310 in November last year together with a publication. I'll talk more about that data for hypercholesterolemia. And we have a best-in-class RNA that we've expanded our platform with the partnership with a company called Sirius. And this is an siRNA targeting Factor XI that's in phase two trials.
Beyond that, we have a very exciting early preclinical pipeline targeting Lp(a), angiotensinogen for hypertension, as well as rare diseases like A1AT. We're actually very excited about our CAR-T platform as well. We presented some data at the end of last year towards the end of December with Zugocel, which was formerly called CTX112. Very, very encouraging response rates in DLBCL in oncology setting, but also very exciting in the autoimmune setting for SLE, myositis, and a whole host of other diseases where you can do an immune reset. We also have efforts, which may be new to most of you, with in vivo CAR-Ts. And here, we have early data in the preclinical realm, which shows that you can actually achieve in vivo CAR-T with a single administration.
Finally, with type 1 diabetes, we have proof of concept data from CTX211 in humans, which showed that cells can survive and be stealth in the body. We're advancing CTX213 as a best-in-class islet cell therapy for type 1 diabetes. Here's the pipeline in a snapshot showing the progress across these various franchises that I talked about. Let me start with hemoglobinopathies. Casgevy was approved at the end of 2023 in a landmark approval. It's now approved in multiple jurisdictions around the world. Our partner, Vertex, has set a tremendous groundwork in commercializing this therapy by setting up more than 75 authorized treatment centers around the world. What you see in this chart here is tremendous momentum for Casgevy between 2024 and 2025. The number of patients that are initiated have gone up 3X.
The number of cell collections, the first cell collections have gone up 3X. And now we're seeing that momentum translated into more cell infusions. We're very happy that we've reached the goal of over $100 million in revenue. The exact number will be disclosed by Vertex on a regular basis, usually in the regular communications. But the revenues are ramping up, and we feel very bullish about Casgevy and its trajectory. And we want the momentum to continue in 2026. One of the things that we highlighted in 2025 was the data in a pediatric population. One of the things with gene editing is you want to treat patients earlier and earlier. The earlier you treat these patients, the less organ damage, the less pathophysiological effects that may happen from the disease.
What we showed that the data are tremendous for children in the 5-11-year age group for both sickle cell and thalassemia. That will significantly expand the addressable patient population as well. What's been really reassuring is the payer coverage for Casgevy has been good around the world. In the U.S., the CMMI pilot has been very successful and adopted now by most of the states. That assures coverage for this patient population. Globally, I think we have very good coverage in Europe. I think we're also seeing momentum around in other markets as well. In the Middle East, the coverage has been universally good in Saudi, Qatar, Bahrain, etc. Overall, we feel very good about Casgevy momentum in 2026. One of the things we do, and this is the same philosophy that's shared by Vertex, is to have continuous innovation.
Once we are very committed to sickle cell disease and beta thalassemia, and we are advancing gentler conditioning agents that would expand the addressable population for Casgevy, and I think these gentler conditioning agents based on ADCs or antibody drug conjugates will be very meaningful in the patient experience, how long the patients have to be hospitalized, and ultimately, I think, how many patients can get Casgevy. Beyond that, we're also quite focused on doing in vivo editing of HSCs or hematopoietic stem cells, and here, what we're doing is taking the gene editing machinery, encapsulated in an LNP or lipid nanoparticle, and directly injecting that into the patients, and that would edit selectively the hematopoietic stem cells, and if you're able to do that, you don't have to go through a conditioning or through an ex vivo transplantation, and that is a core focus for us.
On this platform, we've made tremendous progress over the last two to three years. And here's example data that we're showing in NHPs with a single dose of an LNP mRNA, and we show editing in hematopoietic stem cells. And what you see here is that the editing is durable and kind of reaches its plateau of around 50%, which we believe is best in class for HSC editing. And if we're able to translate this, and I think the translation usually is not very difficult from NHPs to humans, although we have to go through many more manufacturing steps, etc., what this shows is a proof of concept that you could do in vivo editing of HSCs. And that can expand the addressable population meaningfully, not just for sickle and thalassemia, but for a number of other indications.
There are many indications where you can directly edit hematopoietic stem cells, and these range all the way from diseases like SCID or the bubble boy disease to more larger diseases that are not rare that can be addressed with hematopoietic stem cell editing. Now going to the in vivo vertical. We presented data on November 8 last year with ANGPTL3 at the American Heart Association, and we garnered a lot of news because we're entering a new world in the world of heart disease. We published simultaneously in the New England Journal of Medicine, and what we have is a patient coming in and getting a single infusion over two-to-three hours, maybe four hours. You get this infusion of the gene editing components, and your liver cells are edited, in this case, for ANGPTL3.
And within two to three weeks of that editing, you see a dramatic reduction in, in this case, in your cholesterol measures, LDL and triglycerides. It's a one-time paradigm-changing treatment to treat severe hypercholesterolemia, severe hypertriglyceridemia, and many of these conditions that ultimately lead to heart disease, MIs and heart attacks, etc. And so, not surprisingly, got a lot of coverage. And the basis for this type of edit comes from natural history studies. On the left is this picture of a village in Italy, Campodimele, where there was a publication where they saw that nearly 15% of the population had a naturally occurring mutation in ANGPTL3. And these people all had hypocholesterolemia or low cholesterol levels of LDL and triglycerides. And there's an association that they all live longer. So it turns out that they have less heart attacks, less MIs, or less cardiac events.
And the same thing was seen in a 2010 publication, which showed that for both heterozygous and homozygous mutations in ANGPTL3, control for other mutations that were not occurring in these patients, you could see that the LDL cholesterol is lower with one gene that's impacted and then two genes that are impacted. You get even lower LDL. And you want to be at that 50 milligram per deciliter target for LDL cholesterol and similarly for triglycerides. And so what did our data show? We did a dose escalation study with 15 patients. And what we see is that at dose level 3.5 in DL4, which is 0.7 milligram per kilogram of the gene editing material, you get almost complete editing of ANGPTL3. Now, 80% is about the max you can get because ANGPTL3 is produced both in the liver and other organs.
The liver production is about 80% of ANGPTL3. What we're seeing is we're saturating the edit at about 0.7 mg per kg. What that led to in these patients is a dramatic reduction in LDL and triglycerides. At the highest dose, you had almost a 50% reduction in LDL cholesterol. For those, I don't know how many in the room will have, or those listening have high cholesterol, but people try all sorts of medicines, statins, etc. You get 10%, 15% reduction. Sometimes it goes away if you're not consistent. Here, you do a one-time "procedure" of gene editing, and you have 50% reduction in LDL cholesterol. This is very, very powerful. Similarly, we saw a 55% reduction in triglycerides at the highest dose. Now, some of the data are jumpier because the baselines are different for different patients.
Some patients may have high triglycerides but already had low LDL, so you wouldn't see a further reduction in LDL. But what's very remarkable in these data, one, is that even some of the patients had a PCSK9 therapy ongoing, and they still saw a dramatic reduction on top of a PCSK9 therapy, showing that ANGPTL3 is very synergistic with PCSK9. And the second point is there were patients, one of the patients had over 1,000 milligram per deciliter of triglycerides, for instance, which is very hard to control with siRNA. There's an absolute limit to how much you can reduce triglycerides with an siRNA because it's that absolute limit. With gene editing, you don't have that absolute limit. And you saw dramatic control for even patients that have very, very high triglycerides. And overall, it was very safe. There were a couple of patients that had infusion reactions.
There were patients. There was one death, but that was not deemed related to the therapy. It was well after the patient was treated, 180 days later. And this shows that the patients are very serious. They all have had secondary risk of secondary events for these patients. But having a very safe approach for editing where you can have a one-time reduction of LDL and triglycerides, it's quite remarkable and paradigm-changing. And I think it's going to change how we think about heart disease. Obviously, the market is huge because every patient with high cholesterol or high LDL or triglycerides could be an eligible patient for this type of therapy.
But for us, even in the near term, if you look at the very severe patient population, SHTG with hypertriglyceridemia, the homozygous familial hypercholesterolemia, or the heterozygous familial hypercholesterolemia, and you take a subset of those patients that are very serious, for instance, those that have very high acute pancreatitis events, even that is a very, very big patient population. So I think what we're sitting on here with CTX310 is it could be a multi-billion-dollar opportunity and something that could have a dramatic impact on the cardiovascular landscape. Next, we're coming to Lp(a). This is another one which is less known in a way. When you go to the doctor, people measure LDL and triglycerides. Very few doctors measure Lp(a). And it turns out, as more and more studies emerge, that Lp(a) is 6X more atherogenic compared to even LDL cholesterol.
This has been shown with natural history studies, population studies, and reducing Lp(a) hopefully should alleviate any risks or secondary risks. Now, there's a major trial ongoing by Novartis, which is called the Horizon Trial, which is the first sort of trial that has a pharmacologic intervention with Lp(a) reducing siRNA or ASO. And we'll see what the data show us from an outcomes basis. But what we did is we developed CTX320, which is our first-generation Lp(a)-reducing agent. And we saw up to a 73% reduction in Lp(a) levels from CTX320. Now, we have the benefit and luxury of time before the Horizon data come out, and we can decide what our path forward is for a phase two or a phase three.
What we've done is actually develop a second asset, which we call CTX321, which was, in preclinical studies, shown to be twice as potent as CTX320. If the Horizon trial shows that about 70% reduction of Lp(a) is sufficient to have benefits and outcomes, CTX320 is there. But in parallel, what we'll have is CTX321, which should get us to 80 or 90% reduction of Lp(a) levels. If you do the cross-comparison between CTX310 and 320 and 321, based on NHP data or preclinical data, you'll basically see CTX321 can be projected to have a much higher reduction of Lp(a). That'll dictate how, at the end of this year, how we proceed forward with phase two or phase three studies, obviously informed by the Horizon trial. Then we have two additional programs that are very, very exciting. One is CTX340, targeting angiotensinogen.
This is probably the only agent that has shown this level, 53 millimeters of mercury, this level of blood pressure reduction in this mouse model. No siRNA or no other agent has been able to do that. This is just a dramatic reduction of blood pressure. It doesn't happen when there's no high blood pressure. It only happens if there's high blood pressure; you get this reduction. This is going into the clinics soon, and we'll have data on this not in the too distant future. The second one I want to talk about is A1AT. We have a new platform called Syntace Editing, which does very precise editing of the A1AT mutation that causes A1AT, which is the E342K. This is very, very potent.
Even at 0.1 mg/kg dose, we're seeing substantial editing and saturating editing at 0.5 mg/kg dose, which is lower than what we saw with CTX310. And what you're seeing is a complete reversal from the Z-AAT, which is the pathologic version with the mutation, to M-AAT, which is the normal version. And on the right side there. And I think this is a best-in-class therapy for A1AT from a gene editing standpoint. And then I'll talk about our siRNA platform, which is a new platform for us. We did a deal with Sirius Therapeutics in 2025. And with that, we acquired CTX611, formerly known as SRSD107. And this targets Factor XI.
The anticoagulation market is a $20 billion market, but there hasn't been much innovation in this space for a long time because some of the DOACs that target factor Xa have been very good at anticoagulation, but that comes with severe bleeding risks. And there are many, many patients that cannot access DOACs and still rely on heparin or other agents, including vitamin K, because they're not eligible for DOACs. Factor XI only works on one of the pathways that relates to thrombosis, but that relates to hemostasis. But if you target Factor XI, it can prevent thrombosis. And that opens up a huge opportunity where you could have an siRNA agent that's once every six months that does the anticoagulation part without any of the bleeding risk. And that becomes the holy grail in the space of hemostasis and thrombosis. The data presented by Sirius are incredible.
This shows that nearly six months out, you get 93% reduction, 95% peak reduction in the Factor XI antigen, and with siRNAs, it actually is reversible as opposed to antibodies. And that gives us another big advantage over antibodies as well in this class of medicines. I'll skip forward. This is the clinical trial design. We have a phase 2 trial that will have top-line data, hopefully end of this year, in the second half of this year at some point, and that'll be the gold standard in the TKA study, the total knee arthroplasty study. We also have a SAD/MAD design with the CV study, which informs dosing paradigm going forward for this therapy, which also will generate a lot of data this year, and I don't have to belabor the market opportunity with this therapy. This is in the billions of dollars.
This is a very, very large market opportunity. It'll be competitive, but I think we have a best-in-class siRNA. And then going on to CAR-T with Zugocel. If you look at the CAR-T, it's over 13 years now since Emily Whitehead's story and the emergence of CAR-Ts. And CAR-Ts were originally developed in oncology, started with autologous, then there was allogeneic with healthy donors, allogeneic with iPS derived. And then we have in vivo going from viral and non-viral approaches. And I think the blue areas of what CRISPR strategies are. We went with allogeneic with healthy donor, and that's what Zugocel comes from. And the data look very, very good. Because we use editing, they're almost as good as autologous, but with the cost of goods that's much lower and the ease and convenience of an allogeneic.
With in vivo, we're going with non-viral approaches because we think ultimately that's what's going to win compared to viral approaches. This is the design of Zugocel. The two potency edits, the Regnase-1 and TGFβR2, make these very, very potent and almost autologous-like in its phenotype. These are the expansion data. If you look at expansion data, when you put the CAR-Ts, Zugocel in patients, one of the key things is how do they expand. What we show here is expansion in NHL, which is in the oncology setting, compared to expansion with SLE patients, which is in the autoimmune setting. You see comparable expansion. The expansion here is much higher than any of the other allogeneic CAR-Ts or CAR-NKs out there. You're seeing deep B-cell depletion on the right side.
And this is just in line with autologous therapies where you have about a 90-day median for B-cell reconstitution in these patients. This is very, very important. If the B-cells come back in 20 days, you don't have the immune reset. You need to have a deep immune reset, similar to autologous therapies that we've seen data for. And here are data, and there's a couple of elements that are new here. In December, we showed patient data for one of the SLE patients who was in drug-free remission up to six months. And here we show that that patient is still in drug-free remission at nine months. And the second SLE patient also has gone down to SLEDAI score of zero. And by the way, these patients are severe patients. These patients have tried nine or 10 other agents and have not gotten better.
And they take one dose of Zugocel, and they're SLEDA zero. And it's an amazing improvement in their lives. These patients are young females who've had a dramatic change in their life after treatment with CAR-T. In oncology, here are the baseline characteristics. Very severe patients, all high risk, several primary refractory, all with SPDs above 2,000 millimeters square. And in these patients that are very sick, many of them have actually gone through T-cell engager therapies and not responded. One even went through an auto CAR-T before. And then they were treated with Zugocel, and they had complete responses. This is remarkable. I don't think there's any other allogeneic therapy out there that has shown responses after auto CAR-T. And what we have is a 70% CR rate with Zugocel in the oncology setting, which gives us a lot of confidence in moving this forward.
At the same time, the safety profile is very tolerable with a 17% CRS rate, grade 3 CRS rate, and what we're doing is further embellishing the prospects for Zugocel in oncology by doing maintenance with pirtobrutinib. And we have this agreement with Lilly now to use a BTK inhibitor because what you're doing is you're doing complete B-cell reduction with Zugocel, and then you're preventing maturation of any remaining B-cells, and that can give you very sustained and durable responses, and there was an autologous CAR-T dataset released last year that showed that this combination can be very powerful. And I think this is something that could be a very important option for patients. There are a lot of elderly and frail patients, for instance, that cannot take R-CHOP even. They do mini R-CHOP.
There are patients that are not eligible for auto CAR-Ts, that don't have access to auto CAR-Ts. And I think doing this type of model where you do a deep depletion and get them to CR with Zugocel followed by pirtobrutinib can be very important. And finally, what I'll leave you with is our in vivo CAR-T approach. It's a very proprietary LNP system with proprietary mRNAs, sequences, and modifications that we've made for both transient CAR, where we put the mRNA expressing the CAR in the LNP, and you express the CARs that last a few days and deplete the B-cells or any target that you're going after, but also integrating CAR-Ts that can have permanent CAR-Ts based on LNPs without using any viral elements. And here are some snippets of data. And we'll have a lot more of these data over the coming year.
Here is a monkey experiment where we express GFP instead of the CAR. We show that day one, day two, day three, nearly 50% GFP expression and 50% of cells express GFP. These are T-cells that are targeted. That is actually best in class for NHP studies showing expression for transient CAR. What we show is very targeted. On the right side, we show in mouse experiments that if you do the same thing with the liver-targeted LNP, you'd see a lot of expression in the liver. With the control or the LNP that we have, which is targeted towards T-cells, you have no expression in the liver. It's directly targeted immune cells, and you get very high expression.
This is data for transient CAR, but we also have permanent CARs we can make with the same solution where we actually integrate the CARs into the T-cells. So that's very exciting. And then finally, with our type 1 diabetes effort, with CTX211, we saw really encouraging data where in five patients, we had C-peptide production out to 12 months. And you saw that means the cells were surviving without any immunosuppression out to 12 months in patients after implantation. Now, but we were doing this in a device context, and the device did have fibrosis. So I think we want to get away from that device fibrosis and do directly injected cells. And we have CTX213. And here are data with CTX213 in an STZ mouse. This is a mouse that has artificial high levels of glucose.
You see glucose control within 14-15 weeks after implantation. You have C-peptide levels that are in the 1,000 picomole range with a pretty low dose of cells. You already worked out the stealth elements of this with the CTX211 trial. I feel very confident about CTX213 and moving this forward. This is probably best-in-class in terms of C-peptide production. Final slide here. We have a lot to look forward to. We just have one of the things people say with CRISPR is we have so many things going on. The good news is the technology is so powerful that we can actually do all of these in a very cost-efficient manner across franchises. We'll have updates on Casgevy. We'll have updates on in vivo HSC on the Heme franchise. On the in vivo side, we'll have data for 310.
We'll have data for 611. 340 and 460 will enter the clinic. And obviously, with LPA, we'll see how 320 and 321 stack up in comparison to Horizon trial. And finally, with our CAR-Ts, I think we'll have data for rheumatology. But also, we expanded that trial now to include ITP and AIHA and similar to the oncology. So it's going to be a very exciting 2026 and actually a very exciting few years to come. And thank you for the opportunity and happy to answer any questions.
Well, let's start the Q&A session. For those who are in the audience, if you have any questions, feel free to raise your hands. For those joining us virtually, you can submit questions on the portal. Sam, lots of data updates in this slide deck. Lots to digest here. Let's start off with more of a big picture question. How should we think about 2026 focus? There are multiple calls in front of us. Which component in the catalyst timetable do you think investors really need to take a close look at? Which program are you most excited about?
Yeah, I think if you think about the value of the company, you can actually think about it in three parts. There's Casgevy and the commercial aspect, and we'll have continuous updates on that. There are three phase one assets that have shown exciting data so far. 310, we have 611, which is our siRNA, and we have Zugocel, and for all three, the question is a little more data, but also what's the regulatory path forward and what's the pivotal trials we're designing for those. I think that's as a company, those are things that we're working through right now, especially with the FDA and regulatory agencies around the world as to what that path forward is, so that's the second part of the value.
And then we have this third tranche of value or third set of value drivers, which is all the preclinical assets that are going to become clinical assets soon. Like A1AT program could be a crown jewel for us, for instance. It's the best-in-class program that's better than any solution out there that will go into the clinic soon. AGT is something we know. I was talking to some of the KOLs after our American Heart Association presentation for 310. And they were very, very excited about AGT because refractory hypertension is very hard to treat and is actually one of the main reasons for mortality for patients that are older. And so that's another program, for instance, that's in the preclinical realm.
And so that's sort of the framework for how we think about 2026 as sort of this stepping stone pivotal year that tells you what the phase two of the company is going to look like.
So since you mentioned pivotal trial for some of these early proof of concept indications, let's start off with AAT. I think this is where it gets interesting. You start to hear a little bit more clarity on the regulatory path forward there. What's your take for your AAT program as you start to really think about what's that going to look like two, three years down the line? And just layer on top of that, how do you see your program differentiating from others?
Yeah. One thing I'll say on the regulatory front is this FDA, I think, has been very, very supportive of gene editing. I've had a number of interactions with the leadership of the FDA, and they're very forward-leaning. And you saw that with one of our peers' disclosures this morning about a pivotal trial that has 50-ish odd patients. I think that's a very good sign for how the FDA are looking at gene editing. And I think you'll probably see a similar path forward, not just in rare diseases, but also common diseases like autoimmune. We have to work through that. But I think that's, I suspect, that as the year unfolds, we're going to see a lot of regulatory clarity for a number of programs for us.
On A1AT, the big question is, I think a lot of these types of diseases are going to get treated earlier and earlier in life, and what you want, if it's your child getting treated or someone you know, you want the best possible solution for that patient or that person suffering from this mutation or this disease, and what you want is as normal a phenotype of AAT production as you can get, which is in the 20-25 micromolar range, and so we'll see where our data stack up, but from preclinical rat models, which are very predictive, it shows that we may be the best in class. If you take the same dose, 0.5 mg per kg, and say how much AAT production is happening in these rats and just look at everyone else's data, we're far superior.
So I think that's why we do think this is a very important value driver in our portfolio.
So I think if you look back at a year or two years ago, when you look at the same field, competition wants to get at 11 micromolar. That's sort of the magic number that people want to aim at. As we think about the bar, I think certainly the investor community has really shifted away from 11. We're shooting for higher. Where do you think the bar is now for your program? And ultimately, how do you win from the biomarker perspective? Is it 20 or is it 25? Where do you think ultimately you will want to show?
Yeah, I mean, there are a number of KOL calls and things that have happened in the last few months, but the closer you get to 20, the better off you are. Now, does that mean that if you get to 18 micromolar, that's a bad solution for patients? Probably not. I mean, that's actually a pretty good solution compared to where they are now, which is 4-5 micromolar of AAT production, and you want to do that earlier in life because you don't want any of the damage happening in the lungs, and so the higher you get, the better, and I think that's what I'm saying is if you have a program that gets to about 15 micromolar versus one that's 18, I think patients are going to choose the one that's 18. Now, you have to put everything else in context.
What's the safety profile, everything else, et cetera? What's the body of evidence on this trial versus another? But I think our goal, and that's the beauty of the CRISPR platform, our gene editing, is you can try to get near physiologic levels and get better and better and better. So that's our quest with every program. We want to make it better and better and better as we go along.
And then, switching gear into the in vivo side of your story, the cardiovascular space, you're really moving forward with ANGPTL3 and Lp(a). Lp(a), the hurdle seems to be waiting for what Horizon shows, then you'll pick the winner to move forward. Do you see the path forward here as kind of a pick one scenario where you're deciding to pick ANGPTL3 versus Lp(a)? Or do you ultimately think that you'll pick one and then partner off the other assets?
Yeah, I mean, this is a good question. This is one of the things. If you think about the three assets I talked about that have shown encouraging phase one data, we have 310, we have 611, we have Zugocel, and we have LPA. Can we develop all four on our own? Probably not. I think we'll probably need to partner one or the other. But I think we have the luxury at this point with our balance sheet to continue developing these to a point where we have to make that decision, which may not be in 26. But that said, pharma interest is definitely on the ascendancy in terms of cell and gene therapy. Again, there was a period of time in 2018, 2019, everyone was very excited and interested. And then we had a few years where there wasn't as much interest from big pharma.
But I think as we get into beyond rare disease into common diseases, we definitely are seeing a lot more pharma interest. So I think we'll have more optionality than people imagine in terms of what to do with these different programs.
Any questions from the audience?
Yeah, hi. Thank you very much. My name is Charles Bruce. I'm from Mayo Clinic. I have a sort of broader question. How will society afford these? And how are you impacting early development with ultimately being able to afford all of these life-changing treatments?
Yeah, one of the interesting things here is we're actually trying to reduce the cost of health care to the system, and we're working with Mayo Clinic on trials, for instance. With the first generation programs like Casgevy, they are expensive because they're very expensive to make, but if you look at our cardiovascular programs, it's not hard to imagine that these could be priced sub $100,000, and if you look at siRNAs that are priced at $10,000-$15,000 per year, and this is a one-time solution, you're actually creating pharmacogenomic benefit to the system by using gene editing, so same with our allogeneic CAR-Ts. Our allogeneic CAR-Ts now are on a per patient basis, truly less than $10,000 per patient. In fact, we're doing trials now in India with an allogeneic CAR-T because they just can't afford autologous CAR-T.
So I do think one-time interventions, sort of gene editing procedures, will reduce the cost eventually. But we have to be able to continue investing in it in the near term to get to that point. It's not going to be an immediate switch.
Good morning, Dr. Diana Ramos, California Surgeon General. This is very exciting. My one question is, are there any outcomes and differences compared for race and ethnicity? I know there are some response differences for Black communities, specifically for hypertension medications. Do you see any of that with the medications with the CRISPR technology, or are you looking at that?
Yeah, absolutely. There are lots of differences. In fact, if you look at PCSK9 and the identification of PCSK9 as a risk factor, there was a parallel research going on in France and with a physician in Montreal who was a scientist out there in France and then one in Dallas. And the Dallas population had a higher proportion of Black participation in that trial. And there was what was seen is there are SNPs that are out there that are specific by race that render risk differently to different populations. And so this is something that's going to, as we get more and more sequencing, we're going to learn more and more about. And in fact, the thalassemia that you're seeing in Thailand is very different from the thalassemia that you're seeing in the US.
And so we can actually treat all of them differently now as opposed to sort of a blanket trial that says, here's the dose based on general population versus a tailored solution.
Hi, Neil McCallum. Nice to be here. Thanks for taking my question. I'm just curious your take on AI in clinical trials.
Very, very broad question, and what I'll just tell you is what AI is doing in the world of CRISPR. It's actually generally in the pharma world is impacting efficiency of trials, how we think about reducing the cost of trials, et cetera. But for us, the places where it's coming to play the most is protein folding, but now also mRNA folding and mRNA secondary structures when we design mRNA for CRISPR. Then the third one is guide selection or where to interrogate in the genome, and AI is helping. The data sets are not as big as some other areas, but it's getting bigger. So our AI efforts right now are largely focused on the preclinical realm and not yet going into the clinical, but eventually will.
I'll ask the last question here. When you look at the cell therapy space, I think your peers have seen a lot of challenge in getting the credit for things like autoimmune and B-cell lymphoma. What's your take on that? And how do you see Zugocel kind of breaking that barrier where we sit today?
Yeah, I mean, I think it's for a good reason. I think a lot of the allogeneic therapies, the first generation ones, were not as good as autologous therapies, right? And I think we want the best solution for patients. And in the oncology setting, if you kill 99.9% of the cells versus 100% of the cells, the cancer is going to come back. And what we did is our first generation, similarly, was not as good as autologous. But what we did is continuously innovated. And now we have Zugocel, which is a second generation product that seems to be as good as autologous with all the convenience. And I think that's when you're going to see credit is if we can generate more data. And in the autoimmune setting, you get 99.99% of the cells.
That's actually still a very good outcome because it's not a tumor or it's not going to come back as easily. So we are very, very bullish in the autoimmune space. We're expanding trials. We mentioned ITP and AIHA, but we're going to go interrogating other indications as well. I think the immune reset concept is going to be a major way we treat autoimmune diseases.
Thank you so much for your time. That's all the time we have. Thanks for joining us.
Welcome, everyone, to the 44th Annual J.P. Morgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at J.P. Morgan. I'm joined by my squad, Joyce Zhou, Priyanka Grover, and Ratih Pinhai. Our next presenting company is Sarepta Therapeutics. And presenting on behalf of the company, we have CEO Doug Ingram. Doug?
Thank you very much, Anupam. Duchenne expert once said to me, and I quote, "By definition, Duchenne boys do not ride bicycles." This boy here, Max, riding this bicycle in this picture, has Duchenne. This explains why we are so passionate about everything that we do. Thank you all for joining us today. I'll be making some forward-looking statements. Please review our various public filings for the risks and uncertainties that come when making predictions about the future. We're entering 2026 on a strong financial footing with an enormous amount of opportunity in front of us. That's what we're going to talk about. Today, we're going to talk about three things. First, we'll talk about the significant untapped opportunity with our four approved therapies. We'll then move to the outsized opportunity that comes with our next generation siRNA pipeline.
And finally, we're going to talk about that financial footing and the fact that we're in great financial shape, which will allow us to realize our ambitions and fully see the opportunities that are in front of us. Before we do all of that, let's talk briefly about Q4, full year 2025 results. For the full year, as you can see, our total net product revenue was $1.86 billion. Elevidys posted just under $900 million, $899 million for the year. That grew at 9% over the prior year, even in the face of all of the distractions that occurred in 2025. And the PMOs posted $966 million, flat to the prior year, even though there was some modest cannibalization from Elevidys. If we look at the fourth quarter, you can see our total net product revenue was $370 million, exceeding expectations.
The PMOs stood at $259 million, and you'll see that Elevidys posted $110 million. Now, you'll also know that as we tracked to the end of the year, we also tracked into one of the most severe flu seasons in recent history. We had been tracking to flat as expectation would have had us. But in December, there were six infusions that, for safety reasons, had to be delayed into 2026. That obviously reduced the number, but we're quite confident all of those infusions will take place. We ended the year with $954 million in cash and cash equivalents, and that was about $89 million of additional cash over the prior sequential quarter. We have a number of important initiatives. I'm going to talk about at least one of them today to continue the success of our four approved therapies.
You'll also know that previously we had set a floor, yearly floor for Elevidys, of $500 million. I can confirm to you once again that we have a $500 million floor. I can also tell you our intention to significantly grow off that floor and exceed it. I am, nevertheless, going to stop short of giving more detailed guidance today until we track into the year and we see the impact of some of these initiatives. In talking about initiatives, let's talk first about Elevidys. Elevidys is a tremendous therapy that has already brought a better life to over 1,100 boys and young men. Yet, 80% of the addressable ambulatory-only population remains to be treated. That is an enormous opportunity.
We also have a significant opportunity as an organization that comes from the fact that in 2025, for very good reason, we spent the bulk of our time talking about safety. It's now time to balance that and start also talking about the absolute wealth of evidence supporting the efficacy of Elevidys and the disease-slowing nature of Elevidys. We're going to do exactly that. We have a really well-developed plan to do that. We have significantly increased the size of our sales force for better reach. We are augmenting that with a muscular promotional campaign to support it. We have really interesting initiatives with the patient community to accurately and thoughtfully communicate with them. As it relates to the non-ambulatory patient population, you'll know we're not dosing them right now.
Our pathway back to dosing them would be the success of ENDEAVOR Cohort 8, which is our trial for the pretreatment with sirolimus in the non-ambulatory patient population. We're executing that trial now, and you can expect those results at the very back end of this year. So the absolutely primary initiative commercially for Elevidys in 2026 is to broadly communicate the wealth of evidence on the disease-slowing nature of Elevidys. For instance, in 2026, we're going to spend a lot of time talking about the results from EMBARK Part 1, where Elevidys hit statistical significance on each of its secondary endpoints, its key secondary endpoints. Now, you'll have seen in other programs recently, others have been using as a metric of disease slowing, they use percentages.
I think, upon reflection, that is a very thoughtful way of trying to contextualize the impact of a therapy rather than what we often do, frankly, which is give raw numbers, which mean very little to either patients or the physicians they treat. So we're doing that. And using that metric, Elevidys slowed disease progression on each of rise from floor, four-stair climb, and 10-meter walk run in each case by greater than 100%. And the way it was able to achieve 100% is because those boys who had the benefit of being on Elevidys were able to actually improve on those measures, where those boys in the placebo group that didn't have access to Elevidys, on average, started the inevitable decline on those measures that you would expect from Duchenne muscular dystrophy.
Likewise, we're going to spend a lot of time in 2026 talking about the absolutely fantastic results from Embark Part 2, which is the second part of our pivotal trial. In that part of our trial, Elevidys hit every single pre-specified primary and secondary endpoint. And using that same prior metric, Elevidys slowed disease progression on each of NSAA, on rise from floor, on 10-meter walk run by anywhere from 76% to over 100% in instances where boys were actually able to improve when they were expected to have declined. We're going to spend a lot of time in 2026 talking about the wealth of data that comes from our muscle MRI data and muscle health. And I'm going to show you that data in a moment.
If one wonders what can happen to a boy on Elevidys over the long term, I would ask you to look no further than the boys that were treated back in 2018. Because the boys that were treated in 2018, at the end of that study, which, by the way, was a five-year study, were still 7.5 points on NSAA above their own baselines when they started that study. Let me show you two additional pieces of information that are going to play a big role in our initiative this year. Now, this first data is fabulous. This is our crossover data.
It gives us a unique opportunity where these boys were blinded over our entire two-year period, and we had an opportunity to see what happens to treated boys when they're crossed over to a placebo and likewise what happens to a placebo boy when he's crossed over into treatment. And here's what we got. Look at the top line, the dark line. Those are the treated boys. So on day zero, those boys were given an infusion of Elevidys. And they were also, by the way, given a modest increase in steroids per protocol. And you could see they got a lot of benefit, and then they maintained that benefit all the way through 52 weeks. And then at 52 weeks, they were given a placebo infusion. They were also, by the way, given that same increase in steroids that they were given on day zero.
Let's see what happened to those boys. What you can see happen is this. They continued to maintain all of the benefit they had previously received. They didn't receive any more benefit, as you would not have expected, since they got a placebo. By the way, you don't see any steroid effect here. We can just take that concept, that speculation, completely off the table. Now, let's look at what happens to the placebo boys. The placebo boys at day zero, those boys were given a placebo infusion. They didn't get Elevidys. You can see throughout the entire year at every measure, they lagged behind those boys that had been treated. Then at 52 weeks, that is that vertical line, they were given a treatment of Elevidys. What happened? They rocketed up. Why did they rocket up? Occam's razor.
Because Elevidys finally gave them the dystrophin necessary to protect their muscles and slow the course of this disease. Let me show you something else. This is the muscle MRI data between the placebo boys and the treated boys in our study. Now, you need to know something about Duchenne. By the time a boy with Duchenne enters his mid-teens, he has largely had his muscle destroyed and replaced by fat and fibrotic tissue. And yet, when Elevidys' treatment happens, in a short two-year period, you see a significant reduction in fat fraction compared to placebo, a strong indication of much better muscle health. There's inflammation data as well. I'm not showing it here, but it is the same, very similar data. And it's also showing significant increase in health on treated boys versus non-treated boys.
My point of all this, when I think about this initiative and I think about all this data, is that we are going to spend our time in 2026 ensuring that this is appreciated, not by some lucky few, but by all treating physicians, referring physicians, families, and patients who can benefit from knowing all this, and that's going to be a big part of 26 for us. So let's move on to the PMOs. You'll know with the PMOs, we have three approved therapies. We have Exondys and Vyondys and Amondys. Those therapies have been benefiting boys in some cases for over a decade. They've been on the market for a very long time, and there's some things to know about them. The first thing to know is that we've dosed nearly 2,000 boys with these PMOs. There's a lot of experience here.
The second thing to know is that the safety profile of these therapies over this decade has just been absolutely stellar. It's been a stellar, stable safety record for over a decade. The third thing to know about these therapies is, notwithstanding the protocol, which is a weekly protocol, these families love this therapy and are fiercely committed to it. As proof of that, week after week, month after month, year after year, the compliance rates for these therapies are well over 90% over that entire decade period. And the final thing to know about these therapies is now, having been on the market for a very long time and gathering a ton of evidence, there is no doubt these therapies are slowing the progression of disease.
Because they've been on the market for so long, there is an absolute wealth of published real-world evidence on the effect and impact of these PMOs and that the results are both consistent and they're diverse across organ groups as well. Look at this data. The PMOs increase survival by nearly five and a half years. All right? They delay loss of ambulation from anywhere three to four years. They reduce by years, delay by years, the need for nighttime ventilation. They slow pulmonary decline. There's a 50%-90% reduction in assisted ventilation. And look at this next one, a 78% reduction in the risk of reaching an LVEF of less than 55%. That means a slowing of cardiac decline that's directly correlated to mortality. And there's a 30% reduction in visits and hospital visits.
If you look at our recently released Essence results, you see the same thing. They are supportive of our real-world evidence. I'm not going to go over them again. We had an entire call on that, but I'll give you this one snippet. If you correct for the impact of the COVID pandemic on the study, the kids on therapy slowed progression of disease by 30% versus the placebo kids. We're going to take all of this information. We've already asked for the meeting. We'll have a meeting with the FDA by the end of this quarter. And one of the goals of that is to talk about the pathway from accelerated approval to traditional approval. Now, let's talk a bit about our pipeline. As you know, we're very, very excited about our next-generation siRNA pipeline. You can see it here. These are our clinical and preclinical candidates.
They don't include our research programs. The numbers on the far right here are U.S. prevalence numbers. So you can see an enormous opportunity. To contextualize this opportunity, in the U.S., the prevalence for Duchenne is somewhere between perhaps 10,000 and 12,000. So there's an enormous amount of opportunity here. And this understates the actual opportunity because these are U.S.-only numbers. We have global rights. So if you really want to understand the impact that we can have with these therapies, you're going to need to significantly multiply all the numbers on this page, all of which is to simply say that we have a real opportunity to do good by patients and ultimately, by doing that, to do well by our investors. As you know, all of our programs are founded on Arrowhead's TRIM platform.
We did a lot of diligence before we entered into this partnership with Arrowhead, and we were impressed by three things most broadly. The first was the TRiM platform's superior tissue targeting ability. I'm going to talk a bit about that in a moment. We were very impressed with Arrowhead's expertise in building next-generation siRNA. And we were very impressed by safety, particularly as it relates to our latest programs, which are the muscle programs. And I'll talk a bit about that in a second. As it relates to muscle, this is the approach we're taking. We're using an integrin targeting motif coupled with siRNA. The reason that integrin is chosen is because, versus other approaches that are being used, the integrin receptor approach appears to result in much more significant muscle concentration, which could result in significantly greater efficacy and knockdown.
As I said before, we're very pleased by the safety profile of the integrin receptor approach. In preclinical models for both DM1 and FSHD, we see very high NOELs, which, if they translate to patients, means we have a real opportunity potentially to be able to dose escalate to get optimal efficacy in ways that other programs have not been able to do because they've been beset by dose-limiting toxicities. We're also very pleased with the siRNA approach versus other approaches that some other people are taking. And that's simply because siRNA has proven itself over and over again to be a very, very potent modality. In fact, it takes something like 50 times more ASO to match the potency of siRNA. And it's for all of those reasons.
And of course, it's all going to have to bear out in human clinical data, but it's for those reasons that we have hope that both our FSHD and DM1 program can be not only fantastic therapies, but potentially best-in-class therapies. Now, that's the muscle approach. We're taking a different approach with respect to the CNS because here we're attempting to get across the blood-brain barrier. And to do that, we're marrying a TfR1 FAB with siRNA. Now, there's a lot of reason to believe that using the transferrin receptor holds a lot of potential for crossing the blood-brain barrier. But what's also very clear from the preclinical data is the way you go about that is crucial to whether you're going to be at all successful. The first thing is the construct itself. You have to have the right construct.
On the far left, you'll see a divalent binding TfR1 MAB. You can see here it locks into that receptor extremely tightly. Our preclinical data says that it will not cross the blood-brain barrier. Instead, it will just induce receptor degradation and recycling. We don't use that. We use a monovalent binding TFR1 FAB, which our data says should have a receptor transcytosis and then delivery across the blood-brain barrier. Now, that's one of two issues. That's not the entire issue. So the construct's important. The second thing we believe is absolutely crucial is route of administration. And that's why all of our programs, particularly our FSHD and DM1 program, are formulated for subcutaneous delivery. And the reason for that is because preclinically, what we've seen is if you dose subcutaneously, you stay below the transferrin receptor saturation point, and you get constant and robust delivery across the blood-brain barrier.
But as you can see on the far right slide, and this is the actual data that we have preclinically, if you use an IV approach, you get almost immediate saturation of the transferrin receptor, which should greatly reduce the probability of getting across the blood-brain barrier, if not entirely restricting the ability to get across the blood-brain barrier. So we're very excited about the approach. And I'll give you at least a piece of data that tells us that we might be on the right track with this. And this is our Huntington's program. And this is the way we're going about Huntington's. So these first two images on the left make one simple point together.
They simply say this: that trying to reach the deep brain, which is where you must be if you're going to make a difference in something like Huntington's disease, if you're going to try to get there through an intrathecal injection, you're very, very likely not going to be successful. You just don't get a lot of therapy to the right place through an intrathecal injection. On the other hand, if you could cross the blood-brain barrier, you're going to have robust coverage exactly where you need it in the deep brain. And that's exactly what we're seeing. The far right is our data on 1005, which is our Huntington's disease program in the non-human primate. And here we're seeing greater than 75% knockdown in exactly those parts of the deep brain necessary for changing the course of Huntington's disease.
This is some of the greatest knockdown anyone's ever seen in a non-human primate model for Huntington's Disease. We're obviously very excited about this program. To conclude, we're very excited about this entire pipeline that we have access to right now. Let's talk a bit about where we are from a financial perspective. We're in a really strong financial place. We took a couple of important steps last year to ensure that we're on a strong financial footing. In the middle of last year, you'll recall we did a difficult but important restructuring of the company. We retained the expertise to continue to execute. Importantly, we prioritized the highest value program at the same time.
The second thing we did last year over the course of a few steps is restructuring all of our convertible debt or most of our convertible debt so that as we sit here today, right now, we have no significant debt overhang throughout this entire decade. I can tell you that I can give you some broad numbers. I'm going to be careful because our CFO, Ian, wants you to know these are all very tentative. We're still working through the numbers. But broadly, for this year, we will have profit again, I want to be very careful. It's tentative. Our non-GAAP profit, if you exclude the Arrowhead transactions and the payments to Arrowhead, would have been just about $400 million. That would be the second year in a row of positive profit.
And we would end the cash, again, absent the Arrowhead transaction, with an additional $330 million or so of cash. As we look forward into the year and then into the coming years of this decade, we anticipate being cash flow positive throughout. We anticipate growing our cash balance even as we fully invest both in our marketed therapies and in this exciting pipeline that we have. And then finally, on that issue, just remember we have an untapped $600 million revolver. And so we have a lot of strategic opportunity and optionality in front of us if we find something that we think would be in the best interest of patients and also our shareholders. So in a strong, strong financial position, we have a lot going on in 2026. There are a lot of milestones. There's a lot of readouts.
I am not doing full service to it with what I'm going to talk about today, but I just wanted to touch on a few of the things that we're doing. I've mentioned already before that we're executing Endeavor Cohort 8. That would be, if successful, our pathway back to treating the non-ambulant patient population. And just at the very end of this year, we'll have those results. I would remind you that the non-ambulant population is about 50% of all Duchenne. We are going to meet with the agency at the end of this quarter, talk about Vyondys and Amondys. And of course, we'll be talking about what that pathway might look like to transition those programs over time to traditional approval. And finally, we have a lot going on in the siRNA pipeline. I'll just talk about a few.
By around the end of this quarter, we'll have the biomarker data. We'll have the safety data, probably some other interesting data and evidence on 1001, which is our treatment for FSHD. We also, around the same time, we'll have the same sort of data for DM1. So those are two extraordinarily important programs for us and for the patient community. And then we've already initiated, well, the Huntington's program, and we'll be dosing patients in our Huntington's program in the first half of this year. So a lot of things to look forward to over the course of this year. Finally, let me reflect for just a moment on the year 2025.
When we entered 2025, given all of the successes that we had had leading up to 2025, given the fact we had four absolutely fabulous therapies that were already approved, we thought 2025 was going to be an easy year. Well, it wasn't. It was obviously not only a challenging year, but in a few times, there were absolutely heartbreaking moments in 2025. But this team that works for me never lost sight of their mission. They never failed to execute. And as a result, thousands of boys live better lives because of them. As we track into 2026, we're tracking into 2026 on a very strong financial footing. We have an enormous amount of opportunity in front of us, both with our approved therapies and also with our next-generation siRNA pipeline. And I look forward to talking to you all as we progress across the year. Thank you.
Thank you, Doug. I'll ask the first couple of questions, but there will be an opportunity for the audience to ask questions as well. Doug, you talked about the challenges of 2025. As you sit here today, could you talk a little bit about where you are with Elevidys in terms of the patient community and reinstilling confidence in the patient community after what was a difficult 2025?
Yeah. I mean, one of the biggest parts of that is really rebalancing. I keep saying doing a better job, and every time I say doing a better job, people like Patrick recoil because, of course, they were doing a great job in many ways in 2024, but in 2025, because of the issues we were dealing with, we spent all of our time talking about safety, and that was the right thing to do and the necessary thing to do, but one needs both sides of the equation. You really need to understand the efficacy of this therapy, and the efficacy of this therapy was getting lost sometimes in those discussions. There is an absolute avalanche of data on Elevidys. It is greater than almost any other program you can think about.
If you don't agree with me, just cast your mind to other programs that are exciting in the gene therapy world right now and ask yourself if they have as much evidence to support them as Elevidys does. So that initiative itself needs to play a role. Now, we can't ignore talking about the safety issues and making sure people understand where things are from a safety perspective. It's not as if we can just ignore that, nor would we want to. We're in good shape with that. First, let's remember what happened last year. There were two fatalities. They were liver failures associated with older boys who were non-ambulatory. You have to contextualize all that. We've dosed over 1,100 patients, okay? And so you have to sort of look at the numerator and denominator. But nevertheless, a very difficult situation.
The good news is a lot has been going on to take what is already a good safety profile and continue to improve it into a great safety profile. For instance, both in clinical practice and in our label, there's enhanced monitoring that's going to happen on a go-forward basis. One of the great things about that enhanced monitoring is it's not very additionally restrictive because really it's just more labs, more important thoughtful labs rather than more instances of monitoring time. That's going to be very, very helpful to make sure that physicians have good insight along the way. The second thing to know is that in the label and in practice, there is more aggressive reaction to labs and the like. We have that in our label. Physicians independently have been looking at that in their practices.
That's going to play a role in increasing safety. There's another thing that we know. It's something that we can't promote to, but we can monitor and see what's going on. And as it sits here right now, about 25% of sites already are beginning to use sirolimus. And that seems to be growing. And while I don't want to get out ahead of our skis, we still have Endeavor Cohort 8 to complete before we are fully confident on the use of sirolimus. There is some data out there. Dr. Soslow presented data on a small cohort of patients that he dosed prophylactically with sirolimus. And it looks very good, very promising. So there's been a lot of things to enhance what is already versus other serious gene therapies, a relatively safe profile. And I think you marry that up with efficacy.
We do a really good job of talking to people about that. I think we motivate folks.
Questions from the audience?
Hey, Doug. A patient advocate that has consulted with you met with RFK in December, posted on social media, said that Kennedy committed to not. I'll just read the quote. Senator Kennedy committed that young men and boys like my son will not lose access to approved exon-skipping therapies. She was talking about Exondys. Have you heard that from RFK? Have you gotten that indication from anyone at the FDA?
I haven't had—no, the answer for me is no. I haven't had direct communication from RFK or the FDA on the topic. I did see the same post that you saw. First thing, understand the background of that, which I think is very positive as well, and I think HHS deserves credit in this situation, which is that HHS and RFK directly appear to be very close to the Duchenne patient community themselves, and as a result of which announced a little while ago, I can't remember, I think before the end of the year, if I'm not mistaken, that Duchenne newborn screening would be added to what's called the RUSP, the Federal Registry, then we'll roll that out across the states, which is an absolutely wonderful thing for them to have done, that speaks to the people caring about patients.
So it does not at all surprise me that RFK would say that because it would be quite illogical to be going out over your skis to get newborn screening in place simply to take away the very therapies that could benefit patients with that newborn screening. And again, I would think that's a brilliant answer. The patient community loves these therapies. The real-world evidence, in particular, is clear that they're bringing a better life to them. They have an extraordinary safety profile. It would be an unusual thing to want to mess around with that from our perspective. So I was thrilled to see that post. I wasn't exceptionally surprised by it, but I was thrilled to see the willingness of RFK to show leadership of the patient community.
Thank you. Maybe following up on that question on the uniform screening panel, what type of impact could this have on clinical considerations and the space overall?
I think it's going to be, I think it's really valuable, first of all. It says a lot. If you're wondering, anyone who's uninformed, it is hard to get on the RUSP. It is one of the most insanely bureaucratic approach processes that can exist. Not a lot of therapies have gotten on RUSP. It is a big deal that Duchenne muscular dystrophy has gotten on the board. In the long run, it's going to be extraordinarily valuable for patients because we know that if you intervene early, you're going to do a lot more good. All of the therapies, starting with ours and any other therapy, frankly, including to the best of my knowledge, any therapy in the mind of a scientist today does not work by reducing damage already done, but instead stops further damage. It is a race against time.
If you can get newborn screening in place and you can intervene early, you can stop the damage. These kids in utero are being damaged. If you did a muscle biopsy on a boy at birth, while you would not know he had Duchenne, you wouldn't be showing it yet. You would see it in his muscles. You'd see it in the muscles. The muscles are already showing damage.
Speaking of. Oh, sorry. So it's going to be, I got excited. I should have, I told you I need to let you hear about it.
You need space for your hands.
So now, let me say it's not going to be overnight, okay? There's a couple of things to know about newborn screening. So the first thing to know about newborn screening is that it has to be implemented state by state. So there is time administratively that goes into getting the newborn screening implemented on a state-by-state basis. We have a team working on that, a wonderful team that's been working on that for a long time. The second thing to know is that we can dose boys four and over right now. That's where we stop. So for us to be able to go out and really talk and communicate and promote to the under four-year-olds, we need to get our label below four. Good news is we've got great data on the boys below four years old. The safety looks wonderful, as you'd expect, in this age range.
And the expression is simply off the charts. So we hope to, at some point in the not-too-distant future, talk to the agency about getting the age limit lowered so that we can benefit these kids with the newborn screening initiative.
Maybe questions from the audience? I want to, oh, yeah, one.
Thank you. Thinking back to Sarepta's discussions with the agency and considering how ambulatory and non-ambulatory patients are different phenotypically, obviously, what's the FDA's stance now in terms of the flexibility of outcomes to expand therapy to the non-ambulatory kids? And then how to best think about combination therapies as development progresses in DMD, especially along the lines of cardiomyopathy and neuromuscular function?
Okay. On the issue of non-ambulatory, so we're not dosing now because of these two ALF cases. We have a lot of hope that the prophylactic use of sirolimus could greatly reduce the incidence even of ALI, which means it would probably greatly reduce any theoretical risk of another ALF. That's our pathway back to having discussions with the agency about getting these kids back on the therapy. It really isn't an issue of efficacy or the like. It's an issue of ensuring that there's the right risk-benefit there. And that's going to come out of the success, if it happens, of our Endeavor Cohort 8. On the issue of combination therapies, I mean, I think that I think the Duchenne is a very, very difficult disease, even with the greatest therapies. And I am biased.
I think Elevidys is the greatest therapy that exists, certainly the greatest approved therapy out there. They're not cures. They do great things, but they're not cures, and I think there's a lot of room for combination therapies to address many elements of what is a complex and difficult disease, so I think combination therapies is actually quite a brilliant idea.
Maybe final question from me here, just on the corporate finance side, just thinking about the levers to meeting your debt obligations later in the decade, and actually, on the top line, how do we think about the key revenue contributors to consider?
Yes, thanks for the question. So for the rest of the decade, obviously, we've taken action to remove any debt overhang. And so conservatively, even with our DMD franchise, we feel we're in great position to fund our investments and to meet those obligations. On top of that, if we're successful with our clinical programs, we do expect to have siRNA revenue at the end of this decade. But again, with our near-term liabilities now removed, we're in a great position to fund our initiatives and move our strategy forward.
And I should say one other thing that I hate talking about, but Ryan loves talking about, which is we've done a stress test. We've done a lot of different stress tests, including even removing the PMOs. And what you would find is that while that would be painful, be horrible for patients, and we'd have to tighten our belt, you'd still be able to address your debt. So did I get that wrong, Ryan?
No, that's correct.
I'm confident that's not an issue, but over-migrated teeth, they did that analysis.
Thank you, Doug and team.
Thank you.