All right, let's go ahead and get started. Welcome, everyone, to the 43rd Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the Senior Biotech Analysts at JPMorgan. I'm joined by my squad, Priyanka Grover, Malcolm Kuno, and Ratih Pinhey. Our next presenting company is Ultragenyx. I'm presenting on behalf of the company, we have CEO, Emil Kakkis. Emil.
Thank you, Anupam, and good morning, everyone. I'm certainly happy to be in a sunny and not raining San Francisco this year. Of course, a lot of people in Los Angeles I know are having a horrible time, but we're happy to be here today and talk to you and give you an update on Ultragenyx. These are our forward-looking statements. Ultragenyx is a next-generation rare disease company. I think this is the year we've really, really arrived as a company. We've been developing ways of doing drug development, ways to change the regulatory process, ways to commercialize, and putting that together with everything we learned from the past. We're creating a next-generation rare disease company that is now at the point moving toward profitability, generating revenue with multiple products and globally achieving that.
I think it's an important moment in time as a company and what I call a next-generation rare disease company. Now, if you look at our what's special about us, there are a number of areas, and I'll highlight just three areas. But one is, what do we work on? How do we pick? People ask me that question. What's the secret to picking high success? We look for potent biology in a bad disease where you're treating the underlying cause. That is our whole secret. And we look at different sizes of population, less important in finding high potentials. It's whether the drug's going to be a transformative change, or even a smaller number of patients can be an important product opportunity, or a large one. But you really want things that are going to change the future in a big way. We're also agnostic on modality.
That doesn't mean we do any modality, but among the modalities we pick, we try to pick the best modality, which means that you're going to be in the best position to have a product that will last for a reasonable period of time. Now, once you've picked a product, you have to get it developed, and that's another area where we specialize: how to accelerate the timeline to go from a nonclinical result to an actual clinical study and approval. We develop adaptive trial designs, how we manage dosing. We look at seamless designs. We develop novel endpoints, both clinical and biomarker-type endpoints, and the unmet need will be the driver that helps accelerate enrollment.
But how we find patients and how we bring them to the table and how we support them in the trials are all a big part of accelerating and managing time, because time and acceleration is the best way to create more value. And to focus on that is a key part of drug development. Finally, how we commercialize. One of the key aspects of this is knowing that finding patients and supporting them well in the rare disease space is both a privilege and responsibility of our business model. And you can do that with a lean, high-caliber commercial team, not a giant team, but a leaner, high-caliber commercial team, to provide that insight and to use modern tools on how to find patients and bring them forth to commercialization. Our goal is to get majority access wherever we commercialize.
And one other key element of how we are successful is to manage post-approval R&D costs. It is one thing I learned early on, is a burden on all rare disease programs, too many post-market commitments, burning up money for several years with very little benefit often to the product or patients. And we designed a single design trial that will cover all needs that our FDA might want, a single trial, sponsored trial, but based on commercial drug, the disease monitoring program. That means our R&D costs fall, and we put the money where it delivers value and allows us to turn our spend to the next product. These are part of what makes us special about finding opportunities, driving them to an approval, and commercializing efficiently. Now, what has that led us?
We've created four approved products in our first 10 years and now have three more approvals coming, bringing us to something like seven, eight products, potentially nine if the Angelman program were to hit, in a period of time where I don't think there's anyone who can beat that from a rare disease or most any other disease area, and that's how the modalities are coming together and generating product approvals and revenue. This is Avery and Addison, our couple of kids with Osteogenesis Imperfecta, one of our really important drivers going forward. I'll talk a little bit about more of those after we look through the pipeline. If you look at our pipeline, we focus on three therapeutic areas. These are the areas where the knowledge and understanding is there and the unmet need is present.
Inborn errors have been a cure area where the biology is really amenable to successful treatment. We have multiple products, three products approved in that space, four products coming. We can develop and leverage our knowledge on these and our commercialization skills and team. We've been building out the bone endocrine space where our biggest product, Crysvita, has been going, and we're following that now with OI, an opportunity to redo the same type of indication in the same doctor space on 90% overlap. And so that'll leverage everything we learned with Crysvita in that program. Newer in the neurogenetic space, we have an Angelman program. We have several other neurologic neurogenetic disorders. These are disorders which are complex but totally untreated, many of them with large opportunities like Angelman syndrome, and that program's entering phase III.
These are three areas we've been focused in and where we are leveraging our commercial as well as our development teams in developing new products. Now, I'll talk a little bit more about value creation in 2025 in three particular areas. We'll talk about the Osteogenesis Imperfecta program, the Angelman program, and then we'll look at the new programs that are coming to filing and launch and on top of our commercial-based business. Osteogenesis Imperfecta is a very important indication to us. Certainly, I trained with it in UCLA, where it was a very big part of the skeletal dysplasia world, was a big part of what they did there. Osteogenesis Imperfecta is a defect in collagen, which results in fragile or brittle bones. But more importantly, it also causes a significant decrease in bone mineral density.
The combination of weak collagen and low bone mineral density makes these patients have tremendous problems with fractures. If you take the three main types, Type one, three, and four, 60,000 developed world patients and very high unmet medical need, no approved products. What we're working on now is an anti-sclerostin antibody, which basically is taking on the normal mechanism of turning on bone production and dialing up bone production in these patients, which is unfortunately depressed. By dialing it up, we increase bone mineral density substantially in a very short time, and I'll show you some of the data for that, and basically strengthen the bones. In fact, in the animal models, you can bring the bone strength to normal, even though they have mutated collagen. We're excited about the potential. This is a fundamental treatment for osteogenesis imperfecta.
The recent update, we have an Orbit phase III trial that's been ongoing. We did have an interim assessment that was done early in the year on that trial. The goal of the interim assessments was to accelerate the timeline. We originally talked about a two-year timeline for this trial to get enough fractures. But based on the treatment effect size that we saw in phase II, we were looking at ways to accelerate. IA-1 did not hit. We were not informed of hitting the 0.001 stringent threshold. Now we're coming up to IA-2 mid-year and final assessment towards the end of the year. So we expect phase III data this year in 2025. And we're confident in the program. We know the trial is going well, progressing well, and that safety is the same as it has been in phase II.
We feel comfortable about where that program is, and we know a new product that's going to change the future for OI. We're currently investing in the commercial supply because we know the demand will be high. We're doing the other work to look at how to prepare for a launch of this product, assuming we get our data this year, then we'll be able to file and look toward a launch next year. It also is priority review voucher eligible. I think it's been exciting to see in patients with this disease that fragility fractures, as noted here by Dr. Gottesman, have stopped. They don't see them anymore. After a few months, we've seen kids have no more fractures and are active and running around.
It's amazing that you could figure out something like this in that terrible disease, because I thought it would never be treatable. And yet here we are with something maybe profound and transformative. We're excited about OI. It's obviously an important driver for our company. The data from phase II showed a substantial fracture reduction, 67%, a very strong result. The median fracture incidence was zero after treatment. Kids like this child with type four had transformative effects where they're mostly wheelchair or walker bound before treatment and are now running around and don't use a wheelchair or walker any longer. The bones are stronger. They can run around and maintain it. It's actually quite transformative. We're excited to see this kind of thing. This is why we get in this business for all of you out there.
This is what we live for, is seeing this kind of result in life. So another program, big driver is the Angelman program. That program, Angelman itself is a severe neurodevelopmental disorder, a number of different problems, again, a significant population at 60,000. We initiated a phase III trial around antisense oligonucleotide, GTX-102, in December on target when we planned. And we're planning to enroll this and get it done here probably by the early second half mid-year. That trial is a critical, important one, but it will allow us to look at now the ability to take an antisense oligonucleotide and alter the expression of UBE3A in the brain of these patients, a very precise scalpel change to gene expression. This is where the future of neurogenetic disorders is going to be, this kind of treatment, not just tickling the neurons with some small molecules.
When you do this kind of thing, you can have fundamental changes in biology. And what is the most amazing is that you can take kids age four to 17 and have their brain start developing, gaining functions that they didn't have, that all those years in stagnation can be turned on in their brains and the patients can start, the lights can turn on, as some of the parents say, and the kids start learning and having judgment and communicating. Nothing more transformative than that for people in the field and as a medical geneticist to be able to do that, change the future of developmental function in a kid. So we're excited about that program. Our ASO is the most potent ASO, clearly, and we think we'll be the best in class. The phase III Aspire study is enrolling about 120 kids.
We will push to get that enrolled as promptly as possible. We're going to add on another study, the Aurora study, which will be in the other genotypes and other age groups to cover the full label, and we expect that study to get going early in the year. This study will be a one-year study, so this year will be about enrollment, getting steady conduct, and we'd expect data coming for this next year. The Angelman program, we put out data earlier on the Bayley cognition score, which will be the primary. This is the GSV version of the score or the raw score showing very similar, but the power in the study is excellent. We're able to detect this Bayley change.
But in addition to that, if we look at multiple domains, let's say in the multi-domain responder index, we can see improvement across cognition, communication, sleep, behavior, and gross motor. And I think to be able to see all these developmental functions and many of them happening in the same patient, I think is an amazing thing. So that's the Angelman program. Now, if we get to where we are in the adding new products, new revenue, the Sanfilippo Syndrome program is a really important one. I've been working in the MPS field for a long time. That is one of the major areas I'm known for, certainly working in MPS. And the Sanfilippo program, which was at Abeona, was going to get dropped because of difficulties with the regulatory process.
We decided to pick it up because we felt it was time to fight for this and get it done. We've been able to do that. This is an AAV9 gene therapy for a fatal lysosomal disease that primarily affects the brain, which these kids get diagnosed at two to six degenerate. By the time they're teenagers, they may be bedridden, non-responsive, and spend years before they die. The therapy is simply an IV therapy at not a particularly high dose that is able to deliver enough enzyme which cross-corrects other neurons in the brain that showed a substantial improvement in heparan sulfate. That heparan sulfate basically is a correction of the underlying biochemical defect. We were able to get the FDA along with our other companies through a conference to accept the Aspire marker for accelerated approval.
But though we were seeking accelerated approval and we did file the filing in December, we have the clinical data to show the clinical benefit as well, which will help us downstream with reimbursers. I'll show you that data in one moment. We are investing in the commercial supply to have product available. This is an urgent indication. These kids are going to die. It's a lot more like SMA, and we know the parents have no other choice. And this is a thing, and they've been waiting and are so relieved that something's finally coming for Sanfilippo IIIA. The data we already have in hand shows you here persuasive statistical significance showing the difference between the treated patients and the natural history. As you can see, there are a 22.7-point difference, strong persuasive statistical significance.
If you look across several different clinical endpoints, they're all very positive. So we feel we have a great case of showing how this Aspire marker predicts clinical outcome and hopefully transform the field, not just for Sanfilippo or MPS, but maybe for all the other neurodegenerative disorders which have been stuck and many of those programs which have been canceled. Our next program that's coming to file is DTX401 for Glycogen Storage Disease. This is a horrible disease of glucose metabolism. These kids absolutely are struggling to survive with using cornstarch. These kids' livers can't release glucose from their liver, so it builds up as glycogen in their livers.
But that seems like a small thing, but it turns out if you can't regulate your glucose, it means you don't have that safety net that keeps your body and your brain from crashing when you don't eat or something happens. And the only way these kids survive is by taking a slurry of cornstarch. An example is that young girl. This is what she takes every day. I'm just showing you what it is. It's seven glasses. The average patient takes about a pound of raw starch as a slurry, a pound a day. Just imagine doing that. But it's more than just taking starch. It's taking starch with a gun to your head, knowing that if you mess up the starch and don't take the starch, the gun could go off and you can get hurt or die. It's that kind of stress level.
So when people tell me, "This is not urgent. You're just trying to replace starch," it's about not feeling like every day you're worried about dying. And one of the parents at the Rare Affair last night had never been away from her three-year-old kid with this. And she has three caregivers going 24/7 in shifts to take care of a kid when she's not there. But she's the three caregivers on a 24/7 shift, all right, just so you understand the intensity and fear of this thing. And that's why the trial's enrolled, because patients want to get out of this dangerous mode. They're surviving, but they want to get off this treadmill. They want to put the gun down. I'll show you the data in a moment, but we're expected to get the BLA submission mid this year. We're manufacturing in-house now.
We moved it in-house, which gave us some delay, but it allows us to control it and reduce our costs. And this program is also PRV eligible. It will leverage along with the Sanfilippo program, our inborn error franchise. We showed persuasive statistical significance of reduction in cornstarch intake and a number of other secondary endpoints, which I won't go into. More importantly, when you look at these patients, when they know that they've gotten the gene therapy and they get their glucose values, they're able to titrate even better. And the crossover patients who know they're treated or are able to get access, because you couldn't give them access during a blind study, are titrating their sugars twice as fast even as in the control trial. So we feel good about where this is going.
We have strong data, and we think this will be an approvable product in our mind. And we also think it'll be transformative to be able to know that I'm not going to die tonight if I forget something. And many of the patients don't have to take starch at night any longer. And their liver, as we can show in their tracings, stabilizes. Instead of falling like a rock to zero, they just turn the corner and they stabilize. That's what we all take for granted, but for them, it's a matter of life and death. So when you take those two gene therapy products, well, Sanfilippo this year with our expectation, on top of a base business, we've been showing steady growth.
This year, we're putting out somewhere in the $555 million-$560 million revenue, which beat our guidance, which was updated in August, heading to what we expect next year to be $640 million-$670 million, and with enough revenue growth to put us on path to our profitability, so this revenue growth is based on a number of factors. Of course, the U.S. Crysvita in North America has been very, very important. But now we're building out our Latin America business with Crysvita revenue in Latin America being a really important contributor from Canada, from Turkey as well, with other products like Dojolvi, which is both Canada and Europe through named patients, and now Middle East contributing to that product.
And Evkeeza in Japan, in addition to Evkeeza in Europe, are also adding to the revenue flow by having four products now in multiple territories, pulling revenue and it's starting to accumulate out. And we continue to grow our revenue, I think, at a terrific rate, steadily now for multiple years, putting us in great position, I think, for the future. And if you look at where we're headed, we're heading toward full GAAP profitability in 2027. And that's what I mean by arriving. When you can finally see that, that you're going to get there, that you're in control of your future, I think it's an exciting thing. But we're not just going to go across. We're going to have fairly large products arriving in our portfolio, which will put us in position to grow past profitability and really soar past it.
We're, of course, in the meantime, working hard in expense management. We have a number of INDs we have teed up but haven't put into play to manage our burn, but they're there and ready to go. We are making investments in manufacturing for all the products that are headed toward launch because we want to make sure we have adequate supply to drive those approvals and commercial launch. Overall, in cash, year-on-year net cash use is going down, as you'd imagine. And we will also have potentially three PRVs. Although the PRV law did not get reauthorized, these PRVs will be we expect to be approved before the grandfather. So we'll still get these. They don't depend on reauthorization to get, which will give us a significant amount of non-dilutive capital. We have $740 million in cash.
$745 million combined with the PRVs and stuff we have puts us in position to get to profitability without doing a follow-on offering. We also do not have any debt. We're proud of that. What do we expect for 2025? UX143 is obviously the big news, phase III result. We're very confident in the program and what it's doing for patients, and it'll be a transformative product. Sometime this year, we'll be getting phase III data for UX143. GTX-102 will head to fully enrolled study, initiation of the Aurora study, and that will come to a data result we expect next year. That's Aspire's exciting stage. UX111, it was filed December. We'd expect to have a PDUFA date middle of this year, and that will lead to potential approval in the second half, which would give us a product we will be launching.
We know that that product needs special care and launch, and we're going to be developing a proactive therapeutic approach in our medical affairs group to be able to be there, help, and drive, and we'll also have worked extensively on the reimbursement strategies to make sure that we don't get hung up with reimbursement for that program. 401 is at the BLA filing stage, would become a 2026 approval, and we have other programs, 701, 301 in phase III. Still work to be done there, but I would say 143, 102, 111, 401 are the big movers of the year, so where are we at? We have had outstanding commercial and clinical execution of the company. There are very few companies that have the high success rate we have in this timeframe.
In the last 10 years, with the year ahead, we will have on the order of seven approved products, which would be, I think, extraordinary for the 2013, 2014 IPO class. We have a number of near-term catalysts, which we've gone through, three potential approvals in the next year or so. Revenue growth, a base business that's growing beautifully, combined with expense management, put us in position of getting to GAAP profitability in 2027. So I think as a company we will generally arrive as the next generation rare disease company and change the future for rare disease patients. Thank you.
Thanks, Emil. You want to introduce who's on stage?
Yes. Let me introduce who's with me today. Howard Horn is our Chief Financial Officer, and Eric Crombez is our Chief Medical Officer. Just want to remind top talent. They're very important in all of this.
I just want to remind everybody that there's kind of three ways to ask a question, right? Old school, raise your hand. I'll call on you. You can submit a question through the portal, and/or you can just email me, and I can ask on your behalf. But I guess, Emil, I'll start. There's this thesis out there now that you've gone past the first interim to the second interim that somehow the probability of technical success is now different for the ORBIT study. Do you agree with this? Where would you push back on that?
No, no. I completely disagree with that. The idea of the first interim was simply to try to see if we could accelerate further. It had nothing to do with that. I think the timeframe and how much of time exposure was the question, how fast they're going to separate, and they needed very extreme, rapid separation, but the truth is that we know what will happen between six months and one year of exposure because we already have that data and we've presented it to people, so we feel really comfortable that this is going to be a successful product. The question of how fast we can accelerate. Remember, it was originally a two-year type design, and we've been pulling it up, so it's really more about not about PTS, it's about how fast we can get to the success point.
So we feel very comfortable that either the mid or the end of the year we'll be hitting the trial. We know the drug works very well, and so we're confident in it.
Yeah, question in the audience.
Yes. So there's a lot of debate and concern about GT's scalability and development for rare diseases. Because GT treatments require to tailor to the regulatory approval and the complexity is much more. So one of the avenues is companies focusing on rare diseases. What is your idea of how to make it more scalable? Or do you prefer more platform approach to treatment?
The question is, is the rare disease model a good business model? Is it scalable? I think it is scalable, but there are certain features to what you have to do. One, you got to manage the timeline. You have to be aggressive on the timeline. You can't spend eight to 10 years on developing an indication. The biggest hit to rare disease models is if you take too long. If you take too long, then the return for these smaller products may not be enough to make up the loss of time. What we do when we prioritize projects is we look at not just cash spend and budget, we look at NPV. When we make a decision, if someone says, "I'm going to save $50,000, but I'm going to lose $10 million NPV," that's not a good trade.
And so you have to look at value and time and how it affects it. And that discipline is very important. So that's why I talked about. I'm showing you this because here we are. We went public in 2014. We had our first approval two, three years after, two approvals, in fact, and now have four products approved and three more coming. So in a period of from 2017 to 2024, a seven-year period, we'll have seven approvals is our expectation. That's what you have to do. You do have to be really efficient and think about time. I think the other thing is understanding the true choices of the needs. See, a lot of people focus on things that look like a lot of patients, but then again, the unmet need is complex because of commercial competitors and things. You need a big field force or something.
We focus on mostly first-ever treatments because the high unmet need is high and you don't have a lot of other competition, other factors to deal with, which I think gives you a greater probability of success in the model. So those are a couple of features. I think the other thing, you've got to be really good at regulatory. I'm involved in a lot of regulatory work. You have to be really smart about regulatory and understand when the FDA says something, you don't just say yes. You understand why they're saying it and you come up with the right answer. Sometimes, and I was at yesterday's rare affair, I told them, if the FDA doesn't agree to your phase III, it doesn't matter. If it's a good phase III, just conduct it because what they're asking you to do is impossible.
So instead of doing the impossible, do what's right. And when you come back with data, they said, "Well, then they said it was okay for approval." I said, "That's the way it works." They won't give you approval of that program upfront. So that's hard for people. You have to be very bold in rare. If you're not bold, you're conservative, it gets hard to do. So those are some factors. But I do think it's a good model. I went back on this slide to say, "Well, there's the model. Is that a good model?" I think most people would be happy with double-digit continuous growth over multiple years and multiple approvals. So I think we can efficiently turn capital into returns. And the truth is our failure rate is very low, so we rarely put money in something that blows up completely.
So far, four out of six, but the next three hit, that would be seven out of nine successes. In my own career, out of 13 programs that entered the clinic, 11 approved. $2.5 billion-$3 billion at least of revenue. All right? So it can be done. Sorry, I went along.
Go ahead. Question in the audience.
Rare.
Real quick, can you elaborate on some of your reimbursement solutions exploring in 2025?
Yeah. So the reimbursement environment for genetic gene therapies, right, it's just different, right? It's single shot, large value. So you have to spend a lot of time on the value story upfront and being able to put that story together. And you'll need a lot of people in the field that know how to work with payers. Just like we've done our other launches, we'll go to payers pre-approval with pricing ideas and discussion, understand their issues, and put together a plan that will make sense. So we answer the questions upfront and understand what they need from us. And we're good at listening and reacting to what we hear so we get there. I think those are some of the things we're doing. I think the other thing is we have to work at the regional areas because every state will have its own situation.
Every Medicaid program has its own. We have a lot of experience now with all of the different programs and how to work with them, and so those are all aspects we'll have to be proactive on, not wait for the problem, but to go at it before you arrive, so when we go to launch, I want us to know who can get treated, when we can get them treated, and what do we have to do to push forward reimbursement. Because I think for Sanfilippo syndrome, there's no question everyone should be treated. Everyone should be treated. There's just no other answer to that question, so we just have to get everyone to understand why that's true and how important it is to get it done soon.
We have an email question here, which is, how were you notified by the data monitoring committee that you're moving to the second interim? Basically, the question is, I thought you had communicated that you would only be notified if you hit the interim, but not if you did not.
Right. Well, let me just put it. There is a very detailed SOP and process documentation on how to do this because you want to protect the blind of the study. And I don't want to go on all the details of that. But what I'll say to you is they're not going to tell us if it's negative. They're not going to give us the result. We're not going to know anything about what happened. We don't know anything about it, about the inner workings of the data and what was in it. All they did say to us is that they didn't tell us, but we basically heard. All I heard was they had met, and we were not informed of hitting. So it actually doesn't matter that much. The most important thing is that we're protected from any of the underlying data or results.
That's what's really important part in protecting the blind, and so the detail of that doesn't really matter, actually, but we just need to understand that there are very detailed documentation SOPs that go on into conduct of that. We run the database ourselves, but they get blinded data from us, and then with a third party, we're doing the unblind analysis and see it, so we don't actually see, we have the data, but we don't have the unblinding codes, right? So those are all handled in a very explicit and careful way because this will be highly inspected, and it's an important part of the rigor. Data integrity is extremely important.
Questions from the audience? Right here. Yeah.
Yeah. Related to dose delivery, you've got these single injection therapies. On the medical device side, is there any innovation or additional care that you're doing to ensure dose delivery? Is there anything that you're doing that's proprietary on the innovation side?
For the gene therapy, for Sanfilippo gene therapy, which is an IV AAV9, the safety has been excellent. The ease has been simple. And so it really hasn't required that kind of innovation at this point in time. I think from that standpoint, I think it's a really excellent IV gene therapy for a brain disease. In antisense oligonucleotide neurotherapies like Angelman, where you're doing recurrent treatment, it's actually more of an issue of delivery because you're actually doing it repeatedly. Our goal there is to get approved on an intrathecal injection. However, once we make it work, we can then look at devices that might enhance and make the regular life of the patient treatment better by not needing any anesthesia or sedation by having a port or other type of device.
So we're going to look at that kind of thing for ASOs for long term, and then potentially other lifecycle management initiatives, certainly. But for the gene therapy for IV, I don't think there's much that we need to do.
We have a couple of portal questions here, which is, can you remind us of what % fracture reduction you need to see in the placebo on a placebo-adjusted basis to hit stats in interim analysis two? And do you plan on sharing the baseline characteristics for patients in ORBIT prior to interim analysis two?
Yeah. So we've assumed for all of our powering, I think. I don't know if you want to start it. Maybe you can finish it, Eric. We've been assuming 50% power, 50% fracture reduction, relative fracture reduction. But the interims are really more about how many fractures are happening, not really so much about the recruitment rate, right? It's dependent on how many events you're having that will help decide how fast you can finish. That was the issue. But I don't know, Eric, is there anything else you want to talk about in that?
Right. It was just really based on that really outstanding phase II data that we've seen that allowed us to really look at that in a new way and add these interim analyses. So when we're, and again, with the nuance with the FDA and the primary endpoint, when we're looking at all fractures, including fingers, toes, face, and skull, we looked at them coming in with an annualized fracture rate of one, excluding those at the ask of the FDA, it goes down to 0.72. So those two numbers with those patients' baseline kind of allowed us to model what type of fracture rate we would expect to see in the placebo group.
Questions from the audience?
The rate we actually saw was 67%, and that was maintained. So we're above what we powered at. So it's just a question of that times fracture number.
Maybe more of a medical or a market research type question from the portal, which is, does the location and type of fracture pattern for type 1 and type 2 OI patients differ?
I don't think so. I don't know if Eric, you want to say anything about it?
Yeah. I mean, I think the key there is type 1s are much more mild than types threes and fours. And the location and pattern, I wouldn't say really differs. It really is the number of fractures and whether it takes any amount of trauma or it's really fragility type fractures. With the types threes and fours, I mean, we're talking about fractures from rolling over in bed during sleep, transferring from bed to a chair, chair to the car. So it really is the number and then the amount of trauma it takes to fracture there.
There might be one thing I just thought of, which is the vertebral column. Because the threes and fours tend to get cumulative vertebral column morphometric fractures, which lead them to have short spines and nerve compression and often end up wheelchair bound for that reason because of pain and other aspects, I think it's just a question of severity. I think three and four are just more severe, and that in the spine, it becomes irreversible. One of the hopes of the COSMIC study was to look at those really young threes and fours and hopefully see if their spines don't collapse. Because I think that would be the greatest thing is if they don't collapse, don't get cord compression, and then are not all in wheelchairs by the time they're five, six, seven years old.
This is another sort of market research question. What is the feedback basically on bisphosphonate in any treatment in OI, and how could setrusumab be a paradigm shift?
Maybe I'll start and maybe Eric can finish. The bisphosphonates are used off label because these kids are sick and they're trying everything they can. Now, the fracture data from historical fracture studies was a point estimate of about 20% reduction of fractures in the two studies that succeeded and the three studies failed. So the fracture reduction in the formal studies has been modest. Some doctors think it does better than that, but I would say I'd look at the randomized studies that really know the numbers. But clearly, some people feel better. The reason they're using, I think, is more about feeling. I don't know if you have any thoughts on that.
Right. That's exactly why we designed and put into place a Cosmic study. I mean, that really gives us a head-to-head data set that if anyone wants to have the debate on the effect of bisphosphonates versus setrusumab, we will have a well-designed, well-powered study to answer that question.
We think setrusumab will be much better than bisphosphonates. So we want to maybe end the story and make bisphosphonates obsolete so we don't have that problem when we get out there, people thinking that you should settle for this. Because bone destruction doesn't get reversed particularly for a type three and four. Who wants to wait it out before they figure out what needs to happen?
All right. Oh, go ahead.
We can use this.
Great. Thank you. ASTEROID had a great spine data. Can you hit with this trial with spine and maybe not as powerful on the long bones, tibia and fibula?
Yeah. So what David is talking about is the bone mineral density change in the vertebral column looks larger, like a percent larger. But it's just because of trabecular bone that you can detect the bone increase. The other bones, like long bones, have a 2%-3%, whereas the other ones were 10% in that study, right? That's what you're thinking about. But the 2%-3% doesn't sound like a lot, but it's actually around the periphery of the tube. So the physics of it are just as important as the long bones. So we don't think there's actually a differential. It just has to do with the physics of measuring bone mineral density and the physics of the bone. So trabecular bone is easier to detect, the bone production. But we think the long bone and trabecular bone will be the same.
But that was a question that was raised. But I looked at the trabecular bone as the best way to detect the effect. And it was about 9% in the adults. In the five to 12-year-olds, it was 29%, right? And the average is 22% of the study. So it's massive. But that change, and when you measure it on long bones, it just looks smaller, but don't get fooled. The trabecular, even small millimeter changes in the trabecular have a physically dramatic effect on bone strength. So the percentage just looks different, but it's a physics thing. It's not actually a difference in bone effect.
Thank you.
All righty, guys. We're up on time. Thanks, everyone.