All right, let's go ahead and get started. Welcome everyone, to the 42nd Annual JP Morgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JP Morgan. I'm joined by my squad, Malcolm Kuno, Priyanka Grover, and Mireya Hall. Our next presenting company is Ultragenyx, and presenting on behalf of the company, we have CEO Emil Kakkis. Emil?
Thank you. Good to see all of you today. It's been my 20th, so it's 42, but my 20th here, so it's great to be here and give you an update on Ultragenyx. We have a big year ahead. 2024 is a big year, a lot of build-up, putting us in good position, and I'll talk a little about that update today. Forward-looking statement for all of you. Now, I think if you look at what we've been doing in our 10th year from going public, we're just coming up to our 10th anniversary of going public. I think we've been the most productive company in the rare disease industry, in the sense that we've got four products for five indications approved in our first 10 years of being on the public markets. I think that is a special accomplishment.
It's a tribute to a lot of things, which I'll explain in a moment, but we've done a lot to get there and are having a big impact on a lot of different types of diseases. In addition to that, commercial portfolio has been growing. We also have six late-stage programs that are in phase III or transitioning to phase III, and we also have four different therapeutic modes of treatment. That is, different ways to treat disease based on their underlying cause, and we've built that all together in these 10 years since going public. Now, when you look at what's the basis for where you want to look at a comparison of what we've done with others, I think it's good to look at some of the really successful companies, companies that have done great good in the area of rare diseases.
Genzyme, of course, one of the originals, but BioMarin, where I was, but one time, Alexion, Elan, Vertex, these are all really successful companies, have done well. But how do we compare in terms of how many years did it take us from IPO to get a product approved? It was only three years, and we actually had two products that got approved. By 10 years, we will have five products approved, and by 15 years, we expect to be somewhere with eight to 12 approvals. Puts us on a very special place in terms of our productivity and ability as a rare disease company. There's a reason for it. It's part of becoming a next generation rare disease company, design and development of your programs and your company that puts you in position to be able to do and accomplish what we've been accomplishing.
Some of the keys to our success shown here, deep scientific understanding. Now, everyone wants that, everyone believes that, but there are some aspects to it in rare that are extremely important, and one of them is realizing that a lot of rare diseases are not really well understood. One of our important tenets, as a company, is that to really study rare disease, you have to understand that every rare disease has at least one major, well-accepted fact that's actually wrong. If you ask KOLs how to do it, they won't give you the right answer. You need to go directly to patients to learn, and then you uncover the truth, how to unlock the development and how to actually get there. That's one of the key secrets of that deep understanding, is getting deeper and closer to patients.
Our success rate, we've put 11 programs into the clinic, nine out of 11 have been successful. So gives you a measure of how that has worked. Our regulatory and development engine is very different from many. We have very different regulatory strategies and development strategies, and how we design to limit the white space, the time, and how do we hedge risk, and how do we manage endpoint development? These are all things... We have a whole department, for example, that develops endpoints that we've created from scratch, something different that's not usually done, and that allows us to get the right people to come up with the right answers and allow us to both develop endpoints and trials that enhance the power and ability to detect and develop data to show efficacy. With those changes, they also help us with speed.
The key thing in how we run development is, we make sure teams are highly aware of the value of their program, not just their budget this year spend. So they need to look at their budget as one item, but they need to look at their NPV cash account. And when you're making decisions, how are you spending from your value account as well as how you're spending from your cash account? Because you might say: Hey, I saved $50,000, my cash, but if you cost us $10 million in NPV by having a two month delay, where's the savings in that? By making those decisions, you actually make smarter decisions because what's really important is the overall value of your product, not the cash you spend. And the truth is, the time in rare disease drug development is more important than the spending.
That loss of time is more impactful than the spending, and usually, we make the wrong decisions to save bits of spending and ruin the timeline, and that's been key to going faster. Just constantly work on reducing the white space and ensuring we do the best we can on time. Finally, once you get products approved in rare, being a global organization is the best way to extract value most efficiently, especially when the programs are smaller. It's very hard to split PNLs and have the difficulties of working. We think that maintaining global commercial enterprise allows you to maximally gain value. That takes a little work, and we've been developing that commercial organization, but we are now in the U.S., Canada, Latin America, Europe, Turkey, Middle East, through distributors in the Middle East, and is our newest addition to our operation.
That allows us to capture maximum value out of our programs, which is really important in how to succeed in the rare disease world. Now, what has that done? If we global commercialization works and drives revenue, what we've been able to do is we've expanded each product in territories and drive the patient identification process and other aspects of commercial, which is unique and different and rare. We've managed a steady growth rate in the 20%+ for now, with our projection this year crossing $500 million revenue, about 20% a year for all those years, and we continue to do so with these four products.
We've put out guidance for this year, continued growth in our programs, growing in different territories or different products at different points in time, but that the synthesis of all that growth in the global commercial gives us the ability to continue to grow revenue and put us on a path toward profitability. But of course, getting profitability also means managing the expense side of the equation. In 2022, we had a peak in burn. We were setting up a manufacturing plant, and we did deals on which involved Mereo BioPharma and, Evkeeza. We spent a number of cash, but that set us up. Last year, we had a significant reduction in our cash, net cash used, and this next year, we expect again to get below net cash used $400 million.
Puts us in good position in the following year and so forth, going forward, to get toward profitability and a path to profitability in 2026. We have enough cash to move us forward and to do what we need to do at this point. Now, if you look at the catalysts of the company and the focus, rare is a big area, but we've decided to focus in three main areas where we think there's the highest value, the most unmet need, and the clearest biology where we can get things done. The bone endocrine area, highlighted by Crysvita and its successes, followed up now with UX143 setrusumab for osteogenesis imperfecta, is a great product to follow on and build that bone endocrine franchise.
And then inborn errors, we have three approved products that, that manage inborn errors in metabolism, and four gene therapies coming forward to manage those biochemical genetic disorders, which I'm very familiar with. Finally, CNS muscle. Angelman is our lead program there, but there's a lot of genetic neurologic disease out there, a lot of them with no treatments. The latest tools are opening the door to actually using molecular scalpel, like an ASO, and going in and tweaking the gene expression of a particular piece of one chromosome and turning on a gene program that causes the brain to start to function. That's what we're seeing in Angelman. That is the power that I think CNS muscle now genes is, is available, and the ability then to move forward and change the future, I think, is quite exciting. We have other programs here.
We're talking about Duchenne and CDKL5 deficiency. Those are both gene therapies. We have others, even a small molecule and some other programs in the neurogenetic space, which I think are, are sitting there ready to come forward. Now, if you look at our pipeline in another way, and you can look at just in terms of the therapeutic modes, the green here represent the traditional biologics. We believe in traditional biologics as a very good solution, particularly in some of these bone disorders, where you're not gonna do gene therapy to the osteocytes. But for those, the traditional biologics are great. Small molecules can be important in this case, it's a muscle disease, but we have other ones for brain disease where there's a missing substrate that we need to deliver, and we develop prodrugs or other versions of drugs that help deliver on the metabolite.
The gene therapy is all about replacing a missing enzyme in these cases, or a transporter in one case. And then the nucleic acid opportunities, particularly in CNS, I think, opens the door to a dramatic effect, potentially on gene expression we just talked about. Now, among that pipeline, there were, there were actually a large number of different population sizes, which are real important to notice. We have ultra-rares and we have rares, and there's a mix. And what we really look for are diseases where the biology is clear and the unmet need dramatic, and where we have a therapeutic angle on how you can treat it. Some of them are ultra-rare, but those are valuable, but they're not as big. But mixed in the portfolio, you need to have some larger ones that give you the potential upside as a business.
In the last few years, we've added three programs, which have put us in position to have that kind of larger upside. And those three programs are here, the Osteogenesis Imperfecta program. We looked around, we think for that OI disease, that a bone production type of mechanism is the right mechanism for that disease. And in OI, everyone thought you have defective collagen in that disease, and that's why their bones fracture. But the truth is, that's not quite right. It turned out that the real reason they fracture, the main reason, is 'cause they're not making enough bone. And in an animal model, we found with both setrusumab and as well as another drug that we were looking at, that if you normalize bone mineral density, the bone strength is normal. That's one of those facts that actually turned out to be wrong.
That the collagen, while it affects the bone, it doesn't make it bad bone. Which means if you just make more bone, bring their bone density normal, it might have a good effect, and we released data now showing that that's very true, and I'll talk a little more about the data in a moment. With the Angelman Syndrome, a patient family group came up with an indication. A woman whose daughter got diagnosed, she found... She was not willing to give up. She had to fight, find a way, and she called me a few years ago, and I guided her. I said, "You need to find an up-and-comer, top scientist in the best lab who's starting his lab, and you raise money for him, that person, and help them, help you find a direction." And she did find that guy, Dr.
Dindot, and they actually developed a drug. Four years later, she tells me about the conversation we had on the phone. I didn't quite remember 'cause I do a lot of those calls. I always talk to patients when they call. I always call and talk. She said, "That's what you told me to do, and we did, and we came back." And lo and behold, we end up buying the product and the company and put it into play. What a good story. Good coming back to good. But there is another example, Angelman, another big program, and Wilson was the last one. When we started the gene therapy franchise, we brought Dimension. We had a lot of choice in there. The small ones are just not gonna work in gene therapy. The commercial potential is just problematic, even if it might work.
But Wilson Disease treatment looked very promising. It's also a larger rare, and so it becomes one of the three larger potential opportunities in front of us for value creation. Now, let's talk about these programs briefly. I won't go through all the data. We had an Analyst Day, and I recommend you look at the slides from Analyst Day to get deep into these stories. Setrusumab is a monoclonal antibody that blocks sclerostin, which regulates bone. When you block sclerostin, the bones make more bone cells, and those bone cells then transform into making more bone. So by recruiting osteoblasts to become osteocytes and making osteocytes make more bone, it's a one-two punch that's absolutely dramatic in ability to increase bone production.
When we looked at all the possible ways to do that, the sclerostin pathway looked like the most powerful and potent, and we showed you this is true. We took patients with OI, young kids whose bones can develop much more rapidly than adults, and showed a 67% reduction in fractures, and that's really after only six months of treatment. That's very early on. They actually continued to gain bone mineral density and continued to gain ground. But we had kids like this type 4 OI patient, which is the more severe one of the more severe types, who was spending a lot of time in wheelchairs, not getting about. He doesn't use a wheelchair anymore. He is running around, and he's fallen and not had fractures. So potential life-changing result.
The doctors who said, "I didn't think you could just make bone and make them well," they're, like, amazed, and that data release got them now excited and realized, oh, wait, this is actually gonna maybe really change OI, and that's really important in driving ahead the enrollment. Where we are right now is working to close enrollment this year and move toward potentially an interim assessment later in the year or following year. So we're very excited about the potential here for OI and driving forward to a product that we think will fit well within our portfolio. Now, the Angelman program we've mentioned, we've shown a lot of data at Analyst Day.
This is a developmental disorder where you're not expressing a region of a chromosome that's been deleted, and we're turning on the paternal copy of that, and the genes are being expressed, and they turn on a system of function. And what is the most amazing is that you can take kids who don't recognize their name, can't understand instructions, who are hyperactive, don't sleep at night, and you can actually cause them to understand what you're saying, follow instructions, hear their name and respond to it, which they couldn't before, that they can start calmly behaving with other kids. The lights have turned on, that they're actually sleeping through the night instead of being disrupted in sleep. And these changes are happening all in the same patient.
These changes, I think, were very compelling, and I would say I've never seen the speed of rare disease drug development, the ability to actually make developmentally delayed children with this kind of impairment actually gain ground. But their brains are intact, it's just they're not functioning well. By turning on this expression, they start functioning within weeks to months. It's quite impressive. Now, if you look at this on an individual basis, we showed you that if you look across the extension data, we showed you here that in these 11 patients that had data, we can show that multiple domains, most of the patients have 2-5 domains improving in a clinically meaningful way.
If you look at the green here, the greens are what's better in a really clinically meaningful way, and you can see how many different types of functions are improving the same kids. To see not just one thing, but two, maybe as many as five different domains, improving in a clinically meaningful way is a transformative treatment effect. This analysis method is something we intend to try to promote with the FDA, and we'll have a discussion. Our current view with this program is we'll be talking to FDA about the endpoints that we'd like to use, the domains that are important for patients and what endpoints we would use.
Then we'll work our way with the data, come back to them when we hear what they want from us, come back with the data when we get it, which is mid first half, and come back and we'll have a discussion and a phase II about a phase III plan. But the MDRI strategy, I think, is a novel breakthrough way of capturing clinical meaningfulness across many domains. Now, you go to the doctor, you, the doctor tells you, does he talk about one symptom and prescribe all your treatments? No, he looks at all of you. Don't you come up with a plan? So why do trials involve one endpoint with one thing? It doesn't make any sense. The statisticians have controlled the story, but they don't know clinical medicine. This disease has many domains of function.
We should be looking at all of them and incorporating them in our view, what a drug does. If we do this in neurology, we'll change the future where those terrible scales that always fail will be changed by having an appropriate tool that captures efficacy where it exists. That's why this is part of leading the future of rare disease medicine. The Wilson Program released the earliest data now on Cohort 1. We'll have Cohort 2 and 3 data later in the year. This is a transporter gene therapy that'll help restore copper distribution, as well as detoxification of copper. We only do a gene therapy here to be better than chelation, not to be a replacement for chelation. We're in the beginning of this.
It's early, still much to be done, but we're looking forward to continuing the program and getting more data this year from this first dosing stage of the study. Finally, there's four total gene therapy programs. I've mentioned the Wilson program, but the GSD Ia also has a phase III that's been underway. It will unblind later in this first half. That program, I think, is a very urgent one. Patients are stressed about the need to take cornstarch to prevent their glucose from going to zero. They can't release glucose from their livers, therefore, they need it, otherwise they'll die. We follow that with MPS IIIA. It's in where they're missing an enzyme. They have a toxin in their brain and destroys their brain.
Both those diseases will be releasing at WORLD, a WORLD Symposium for data on the MPS III program, and our hope is to get it accelerated approval path with FDA. Both those, I would consider, highly urgent gene therapies for disease, which I think will characterize how they'll launch. Those are the ones where people want to get treated, and they're urgent about it. OTC is a little further back, but another program we hope to finish enrolling phase III this year.
Now, the gene therapy platform is built on a lot of things, but the ability to create the PCLs and the PCL platform is certainly an important part of it. But we've added in building our own first-class plant. Some investors have gone and visited the plant, toured it, and we do provide opportunity to take a look. It is not a mobile homes assembled into a plant thing.
It's an actual greenfield, top-tier quality plant, including two suites that can run 60 runs a year and a suite for doing drug fill as well, fill finish. So it's a complete plant. It is operating now. Last year, started GMP operations and are running, and we'll be moving more things into the plant, taking advantage of a 34% reduction in cost structure, which in the long run, will be. Will pay off importantly for us. So we're excited about the team. They've done a great job. They built this plant during the middle of the pandemic, so that's quite kudos for the team. We're able to do that and get the supply chain done ahead of time. So where are we going from here? I'll start with this, the UX143 bone program.
We're coming close to getting these two trials enrolled, and we'll put a little bit more phase II data update and hope we'll—there may be an interim assessment occur. We'll see if it hits high statistical significance, 0.01. We could see a result later in the year if it works, but it's not quite 0.01, it might be the next interim or another. GTX-102 this year is about the expansion cohorts. Mid-first half, that data, we'll have FDA discussions and probably update where we are on FDA, primarily when we talk about the end of Phase 2 discussions. Wilson will be Stage 1 data in three doses. That'll somewhere in the first half, we'll probably get there, and we'll be able to see how that's going, then we'll look at initiating a randomized controlled trial later in the year.
The phase III data of GTX-102, DTX401, is later first half, and that will be an important milestone for that program and one we're excited to look at. DTX301 is mostly about enrollment, this year. Of course, on top of the clinical catalysts, there are all the commercial products and their continued growth throughout the world, building a base, financial base for the company, which is in a very great place. We're leading the future of rare disease medicine. We are one of the most productive companies or the most productive company based on how many programs we've moved, forth and succeeded on. We have near-term catalysts, including several large ones this year, particularly Angelman and OI. We have...
Those programs could generate tremendous revenue for us and put us in an incredible place in the next 2-3 years. Finally, with continued revenue growth and existing products and expense management, we are in a good position in how we move forward with our cash. That's our story today, and thank you for listening.
Do you want me to join you there or stay up here?
Wherever you want, man.
It looks like you're set up there, so-
All right. I'll take up-
Howard will take the inside, and I don't want to mess up your-
Yeah.
Trade setup. Are you trading on the side here?
Well, market, market's closed.
Oh, I know. Japan is there. I don't know.
I'm also not allowed to trade biotechs.
Oh.
It's, like, the only thing I know.
Oh, really?
Yes.
Well, I don't trade either.
I'm sure I could pick a lot of short positions, but I can't do that.
There's probably some people in the room that'd be interested.
I know.
Can't talk. So, if some of you've been in these sessions with me, three ways to ask a question, right? So old school, raise your hand. We'll call... I'll call on you. New school, if you have access to the portal, you can submit your question. It'll come on this fancy iPad. I will ask the question for you. Intermediate school, maybe, you can email me, and I will ask the question. So, you guys pre-announced yesterday, fourth quarter, as well as provided 2024 guidance. One thing that stood out to me was, you know, given the run rate that you had in the fourth quarter with Dojolvi, like, why the guidance appeared a little bit weak, for 2024?
Yeah, I think... Did you want to answer the Howard, the guidance question-
Sure.
Dojolvi?
I'll try that one. I guess the thing to understand here is there's two underlying dynamics at play. Where we're commercializing the product, we're growing, you know, at double-digit rates. And where we have named patient sales, that's, you know, a lower rate. So those come together to build the single-digit growth for year-over-year.
Right. So the U.S. revenue growth is still linear, continuing. It's just the named patient in the other territories are more limited. But we're excited about Dojolvi. I think it's doing well, and we're still launching in Canada and starting South America. But we're excited about the potential, but named patient is always a little bit more limited.
Actually, also on the guidance, like, how do we think about what you guys are seeing in terms of top-line growth in 2024 versus 2023 with Crysvita, given some of the accounting changes?
I think that's perfect. You mentioned accounting. That definitely goes to the CFO.
Yeah. So I, I guess-
Talk a little louder.
...With Crysvita in 2023 and 2024, you know, in both cases, they're growing in the 20% range. So Anupam, was there something there beneath that you were asking about?
Just with your partner and how the accounting changes.
Got it. Yeah. So, what we described last year and described this year is in aggregate, all Crysvita revenues from all locations, whether it's through the partner or not. So you know, what transpired this past year is that we've passed over to our partner, Kyowa Kirin here in the U.S., commercialization.
Questions from the-
I think the thing I would add is that the switch to the royalty, which is a high 20s royalty, pretty much mimics what our share of the 50/50 profit share, near it exactly. So there's really no step off. It was designed that way five or six years ago. In 2013, actually, that's when we did the deal, and actually came out right. That's unusual. I usually never feel don't get it right, but it actually came out matching pretty closely. So that's why it's not... There's no really a shift, because the switch to the royalty really represents our share of the profit share.
Questions from the audience? Maybe just switching to the pipeline. You've got three important first half readouts. Any guidance on the cadence of which ones will come first and last between GTX- 102, DTX401, and UX701?
Okay. Well, I'll add that MPS IIIA will have data presented at WORLD. So that's... You didn't mention that one, but that's the first one. That's in February, so that's kind of on the timeline.
Okay.
We'll have some discussion with the FDA, and there's a workshop on the biomarker there. It's one of the important things we're trying to do, is drive the FDA to accept biomarker approvals for some of the rare metabolic disorders, and we want to use that as one of the cases to drive forward. We think it would be really important to the gene therapy field that they start accepting more biomarkers. So that's. You'll see some data from that. Following that, the mid first half is probably Angelman, right? That timing. GSD-1 was probably after that, and UX701, probably in that later part of the first half.
Okay. Questions from the audience? So maybe on GTX-102, you and when you showed that slide where you talked about the different domains and-
Mm-hmm.
you know, once you get the data, going to regulators and talking. If you had to put sort of a hierarchy of the importance of domains and the disease and what you would aim to talk to FDA about, how would you characterize that?
Well, I think that... Let me start by saying that I think all these domains matter to patients. Some may matter more to one than another, so when we pick one, we're, we're not really reflecting. For example, for some parents, the sleep domain is not so important because the kid's sleeping okay. But for example, patient C that we presented on Analyst Day, that kid was staying up multiple times every night. They used to, they told me, it's fascinating, that they drive him 60-90 minutes in the middle of the night, driving. 60-90 minutes of driving to try to get him to go to sleep. So that kid, sleep is like the number one thing.
It was disrupting everyone in the family, and when he started sleeping, and we get back, he was on the drug, slept well, then he lost the effect when they took him off. When he started again, within two weeks, he started sleeping again, and the family is just relaxed. He's going to work. So that's their story. So what I want to say to you, it's really hard to pick because they could be interested in receptive communication, like responding to your name, following instructions, which many of the kids do. But for them, sleep was so dominant. So when I say to you, I think different patients have different endpoints as their key. Receptive communication and cognition are important to everyone, and we see pretty broad response if you look at the Bayley-IV Receptive and the Bayley Cognition, right? Those two domains.
They're highly related to each other, though. Your ability to have cognition depends on your ability to have receptive communication, right? They're asking you questions. You're, you know, the two are integrated, but those are a common one. If you had to pick, those two are highly relevant. They seem to be more pervasive in response. So I had to pick them. Those are two that no one would doubt that receptive communication, being able to hear and understand instructions and follow, be able to communicate, in other words, with your family, and being awake and alert and know what... You know your surroundings, know what's going on, I think those are important. Gross motor is very important, particularly some of the older patients that start losing their ability to walk and start getting weaker, that those are, I think, important.
Behavior for some kids is a big problem. Some kids scratch, pull hair, so the parents can't take their kid anywhere or leave them with anyone because the kid's out of control, and people say: "Take him out. I can't deal with him." So I would say there's differences. I would put Bayley Receptive and Cognition probably a little above, but I would say to you that sleep, behavior, gross motor, for some patients, is a big, big deal. So the truth is, I think it's still better to look at all five or six domains rather than one or two. But the question you're asking fundamentally is, what if FDA makes you pick? That's what you want.
Yeah.
Then which, what would you pick, you know? So I've given you one idea. I think the Bayley has a lot of history data. There's a lot of natural history data. We know the Bayley score doesn't really change much in natural history.
Mm.
Like, very little. We showed you that data. It barely changes. So from a placebo-controlled trial, we feel good about that one as one that would not have a lot of random movement. It would be one that would should be readily controlled.
As a follow-up to Anupam's question,
Have you noticed any lag time in some of these domains, in terms of improvement or for every patient?
Well, there is some differences in every patient, for sure. The fastest is sleep. It seems that patients have sleep problems. They start sleeping within two weeks after the first dose. So that effect is very rapid, and if you saw it, the sleep went up really well, and it kind of reaches a plateau. The, the behavior problems kind of go along a little bit with sleep, but they're steady. The receptive communication and cognition appeared to be kind of steady over the first six to nine month period, and it... They appeared to be continuing. If you look at the graphs, they continued to gain ground over time. Gross motor appears to be a little slower, fine motor. Some of that might be because they're more complex things that they have to do, the coordination and combination.
But I would say to you, if you look at the curves, within the first eight to nine months, all these domains are moving. And the truth is, that's surprising because most people thought that if you fix the brain function, it's gonna take someone at least a year or two for that to translate into actual functional outcome, right? To be talking about weeks to months of a brain changing function and gaining complexes is already amazing. So I actually think the fact that we can do a study less than one year and show the... And we believe, show the difference, I think that's, that's amazing. Because most of the people, including ourselves, were thinking it might take two years. So we were running around trying to deal with the biomarker idea, right? But it turned out that the clinical response was way faster than most people expected.
That's the good news, and we've spent less time on the biomarker because honestly, if the clinical response is there, I don't need the biomarker.
Questions from the audience?
Yeah. In general, what do you expect the FDA will do? Before we talk today, right? So,
Bayley has some history, but the FDA, you remember from My Big Fat Greek Wedding, the man's the head, but I'm the neck. All right, the FDA may be the head, but I'm the neck, and I make them turn their head wherever which way they want to turn it. So that's my job. Our job is to turn their head to the right scientific answer and show them why. And I would guarantee you, just because they say so from their own experience, doesn't mean it's right. Sometimes they are right, but sometimes they're not. And in this case, you know, I wanna make sure we're doing the right thing, but.
But given the heterogeneity of the population that you're describing, even in this talk, right? What would, what would be the incentive of the FDA to make you focus specifically on Bayley versus like more of a composite where you can, you can actually understand the different domains?
One of the things the FDA worries about is the procedural, historical, validation, natural history kind of story, right? For Bayley, there's a lot more historical use. There's a lot more established understanding of the magnitude of effects and what they mean. There's, there's not a lot of products approved with Bayley. There's very limited, but I think they would see it as, let's say, a more well-developed state. So that would tends to attract them as opposed to a brand-new endpoint they haven't seen. This is a harder lift. So for sleep and behavior, we may have to work on with either the AS, Angelman Severe Assessment or a specific scale. Those are scales they'll have less experience with, so it takes a little more lift to get them there. So among a well-established, well-known one versus newer ones, less well-established, that makes it harder for them.
That would be the history.
Questions from the audience?
Maybe switching gears a little bit to setrusumab or UX143.
Sure.
Could you clarify your comments about how you're thinking about the interim, an interim? Would you do an interim assessment and disclose it? Or if it didn't hit, like I think you said 0.01.
Right.
This study would continue, and you'll not disclose it?
Right.
Like, how, how does that work?
Well, let me explain. First of all, when we saw the power of the effect, we realized the possibility that we'd hit our endpoint way earlier, and we didn't wanna wait for as long as we thought originally we might have to wait, because the fracture rate was higher and because the treatment effect size was larger. Rather than completely shrink the study in size and go the same length, we left the study still big, although we're gonna shrink it a little bit. But the idea is, let's figure out how to end early if it hits the mark. So the idea is to look at when you have, let's say, 60% of the fractures we would have assumed in the powering. With this level of effect, we think we could have achieved hit statistic significance at 60.
So we'll do the interim, where we think we would be about 60% of the fractures that we originally assumed to be for the total. The timing of that ends up being likely towards the end of the year, the last part of the year. The DS, the data board will run the analysis, and we'll only find out if it's positive. We're gonna set the criterion for them, and the criteria will be for that, and it will be 0.01. The reason to make it strict is if we're gonna shorten the study, including patients just under a year of treatment, not longer, we wanna have a bulletproof story with the FDA. We don't want to have them say: You cut it short, we're more interested in safety.
With a 0.01 p-value or less, you're in a position of persuasive statistical significance, and in fact, a question of—you know, ethics—continuing a trial, keeping kids on placebo with that setting. So that, to me, is bulletproof. We'll do it that way. We also spend no alpha; therefore, we don't hit. The next interim, which will be where all the patients will have definitely more than 12 months of treatment, a few months later. We're gonna spend a little bit of alpha there, and that'll allow us to hit it if we're very good endpoint. But then I think with at least a year of therapy, I'm a little more comfortable we can press the case with FDA. And then we'll continue to have most of the alpha spend at the end to make sure we hit.
So we wanna make sure we hit it. I believe we have a good shot of hitting an interim, but, you know, 0.01 is very stringent, and 0.02 would be an amazing result. 0.01 would still... but would still not trigger the stop. So we're not gonna know. We won't announce it unless something has happened. But I would just say, if we don't stop, doesn't mean something's not working. It just means we didn't hit a very stringent step. The next step will be a little better, but, we're very encouraged about what we're seeing. So I think the possibility is there, and we'll see.
All right. If there are no more questions, we will wrap up. Thanks a million, Howard.
Thank you, Anupam.
Thank you, all.