Good morning, everyone. We're gonna get started. It's great to see all of you here at the St. Regis and those of you online. Beautiful, beautiful day in New York City to be together and do a traditional analyst day. We haven't done one for a while, but we're at an important inflection point for the company. With so much going on, we thought it was an opportunity to really get you updated on all the pieces of what's happening with the company, which is what we'll do today. So, and on your sheet, you'll see an agenda on the table there, and we'll basically, I'll be starting with some opening remarks.
We'll do a deep dive into UX143 for OI, a deep dive then into Angelman syndrome, and after a break, then we'll do a deep dive into our gene therapy franchise, including the Wilson and some initial data on Wilson for all of you. So I think it'll be a very full day, I think a very exciting day because we'll have so much data coming out for you today, but also to tell you a little more about the company itself, to get you oriented who we are as a company since our IPO in 2014. This is our forward-looking statement. Ultragenyx is leading the future of rare disease medicine. What I mean by that is we're not just developing rare disease drugs, we're actually changing the world of how it's done. We're establishing new policy, new approaches to study design, endpoints.
We're trying to change the field around us so that all companies working in rare can be successful to maximize our impact on the rare disease world, and that's what we mean by leading the future. By doing that, we also can attract the best people and develop the best products and get the best opportunities for developing the first-ever treatments in the rare disease world. When you look at us as a company, you think about the 2013, 2014 IPO class, I mean, those were the hot years when the markets opened. How many companies now are at five commercial programs from that era? I think we're alone in that regard. Five commercial programs, globally commercializing, with revenue growth still growing in the 20%-30% range for these programs. We're a strong commercial company now within that short period of time.
When you think about our clinical development products, we have put nine programs in the clinic since forming. nine programs that have been successful in clinical data, nine out of 11 total. We are highly efficient at picking, developing successfully therapeutics, and that I think there's no one that can beat that number. So I consider ourselves the most productive rare disease company in the business. Our ability to pick, find, develop, and execute, I think is second to none, and that ability is what creates value for us, but also brings forth first-ever treatments for rare disease patients. When you look at the group of rare disease companies out there, these are the best names in rare disease I think: Vertex, Alnylam, Alexion, Genzyme, BioMarin, where I was some time ago. These are their numbers from years from IPO to our first approval.
Number of approvals, 10 years. Number of approvals, 15 years expected. This is where we are as a company. Our first approval within three years of going public. We'll have five approvals by 10 years, and with the slate of products in front of us today, we expect to have something like 8-12 approvals during the first 15 years post-IPO. So I think we can say very definitively on the analytics that we are the most productive rare disease company in the business. What are the keys to our success? What makes us special? First thing comes in clear science. Potent biology in a bad disease. We work deeply, we respect the people that know, and we go deep to what's happening, to really understand what will work, what can work.
By careful success, it means we're gonna put money toward things that have a chance of changing the future for a disease. In our development processes, we focus on time. We look at time, and we look at the fact that every week lost has value lost, and you lose a year, a week at a time. We look very aggressively at how we manage time in our development programs, how to ensure we don't lose time. That includes adaptive designs, where we can go rapidly toward figuring out what the right dose is or fusing phase II and phase III, so we go quickly into the phase III stage of a program. All these tactics help control time, and time is one of the biggest problems in biotech, is actually taking too much time.
Key to making that all work, both in the science and on the development, is having a great team. Certainly, since the beginning of the company, I spent my time finding, recruiting the best rare disease people in the business throughout the company, and that's just not just in the clinical development area or statistics, but in all areas of the company, and that building a team that believes in doing good and doing well, the team that believes in the culture of collaboration, the mission, those are people that can fight to win, and the kind of experienced management team that succeeds when others can't. Because our business is hard, and it takes more than just hope to succeed. With that great team, we're able to get things done, figure out a way, and find the possible way to succeed even when it may look difficult.
So if you look at beyond the development side, commercialization is that, well, we can develop the product and get it approved. In the end, we haven't done anything until we've delivered it to patients wherever they are. We've led the commercialization now of Crysvita as a blockbuster product. We did that with a very innovative design, with a field team that finds patients wherever they are, lost to follow-up, and help feed them into the system so we can actually then commercialize and do it effectively. And that program continues to grow with our novel way of approaching commercialization. We've navigated more first-ever launches, first-ever treatment launches than most any company, including most recently Dojolvi. That takes insight and knowledge of how to do that, how to find patients and put them on drug, and develop the systems for that.
As part of that, we wanted to be the most respected company in the industry by payers, doctors, and patients, and that comes through how we handle ourselves in the field. We provide compassionate access, for example, to our treatments when they're needed, showing that we care about patients getting access. We did that for a number of programs, including Dojolvi and Mepsevii. We support commercially patients, so that they get access, and they don't not get treated because of financial things, including co-pay support and even free access where necessary. Our team is excellent at getting reimbursement, but we want to make sure, and we do in the US, guarantee 100% access, and we can do that because we're good at what we do.
But because we do that, we gain the respect of people that we really do care about the final story, which is patients are getting treated and not going broke because they're actually getting treated. We've taken that philosophy globally and are a global company now, being able to deliver our therapies not just in North America, but South America, where we have shown great success. In Europe, we're beginning and doing great work now, and most recently, we've added Japan as well as a new territory for the company. If you look at our pipeline, we have six later-stage programs. There's no one with as much as we have. These are Phase III or late Phase II programs, all generating data, all showing success so far. I think it's the richest pipeline in the rare disease business by far.
Among those programs are three large opportunities, each of which, each of which could be transformative for us, any one of this, which would become a dramatic value to us, and all three are working. And today you're going to hear about osteogenesis imperfecta with 60,000 patients and transformative data we've released on the early Phase II study showing fracture healing. We're going to talk about Angelman data, another population with about 60,000 patients, and our most recent extension data on ASO. And we'll talk to you about the first cohort data on Wilson disease today, so you'll get an idea of how that's going. So while three of these individually could be a great step forward, we actually have all three of them working. Key catalysts. Well, today we're going to talk about three.
I just mentioned UX143, GTX-102, and UX701, OI, Angelman, Wilson disease. Those are data today. We have coming, of course, data on DTX401 for Glycogen Storage Disease Type I, and updates on UX111 coming as we do our regulatory discussions on filing. But in addition to that, more coming in the next year. So between now and next June, we are very catalyst-rich. Part of making it work, though, is in difficult markets, the situation is managing the money and the burn. We're doing a lot, and that means it does take the financial resources to do it. But we have been implementing more aggressive financial discipline, including realigning our headcount, restructuring in places to manage and capping headcount, and doing the work we need to make sure we're putting the people and the value investment where the value is.
That means putting some things on hold. We have a number of INDs we've held up until we're ready to be able to do them. By putting the effort on some of the late-stage large opportunities, which puts us in a better position going forward to grow the company, even in a more difficult financial environment. We look at our revenue growth over time. W e, of course have five programs generating revenue, and we expect to be adding additional programs. In our plan, we see ourselves getting to profitability in the near term, and I think that that is a discipline we intend to have as a business. So at a moment in time, future rare disease is here. It's Ultragenyx.
We have multiple modalities, all picked and designed to be the best choice for that particular disease area: an antibody for a bone disease, a gene therapy for Wilson disease. We have major catalysts as we've gone through for multiple key programs within two to three years. We have on deck multiple approvals coming, projecting us to more than $1 billion in revenue in not too long and a path to profitability as a company. That's Ultragenyx in a nutshell. So now we'll work into the program, and I'll introduce Eric Crombez, our Chief Medical Officer, who will talk about UX143 for osteogenesis imperfecta.
Great. Thank you, and certainly excited to be able to talk about this program. It's really not very often where you have the opportunity to work on a disease and a program like this, where you have such a very clear signal across data points in such a short amount of time. We have had the opportunity to share some of this data at the American Society for Bone and Mineral Research. That meeting's been ongoing over this weekend, concluding later today, and we'll have an opportunity to speak with our lead physician there, interviewing some of our important investigators working on this program. Just as a reminder, osteogenesis imperfecta is a rare genetic bone disorder. It does have high unmet medical need with no approved or effective treatments available.
Bisphosphonates and vitamin D are used in some patients, and it does offer some degree of protection against fractures. But what you'll see is when we're looking at the data for these patients coming into the study, and we really looked closely at the two years preceding dosing with Setrusumab. We are continuing to see a lot of fractures. We are seeing a high annualized fracture rate in these patients, and importantly, we're seeing a lot of fractures that are occurring with very minimal activity. These are referred to as fragility fractures. These are fractures that are occurring while patients are sleeping, meaning they're able to fracture bones simply by rolling over or twisting while sleeping. They can fracture while trying to transfer out of a chair. They can fracture while trying to get in and out of a car.
So again, really seeing a high unmet medical need here. Setrusumab has a very unique mechanism of action. You can see here with the cartoon on the right, we have Setrusumab as the light blue, fully humanized antibody to Sclerostin. Sclerostin is captured here by those purple check marks. Sclerostin is produced by osteocytes as a negative feedback loop to inhibit bone growth and bone remodeling. So by essentially taking Sclerostin out of play with Setrusumab, what you're doing is you're enabling your osteoprogenitor cells to come to the bone, become osteoblasts. The job of the osteoblasts is to build bone. They then revert into osteocytes, which makes up 90% of bone. With ongoing treatment of Setrusumab, this cycle repeats itself over and over again, and you can see the laying down of new bone here shown in brown.
I think as we go through the now longer-term bone mineral density and the new fracture data and reduction in annual fracture rate, I think we can say in these patients with osteogenesis imperfecta, it's new bone, but it's also better and stronger bone. Just a reminder about the phase III part of this study, and this is an ongoing phase II/III study. So we enrolled 24 patients with Type I, III, and IV osteogenesis imperfecta. These were patients between five and 26 years of age who were randomized to receive either Setrusumab at 20 ml or 40 ml per kg. Now, what's important here is that we now have all 24 patients at least six months of follow-up, which means we can really look at fractures and annualized fracture rate in a meaningful way.
What we're seeing here is a 67% reduction in fracture rate after at least six months of treatment. And again, that's, that's a very powerful result. When you think about the time, you know, it takes to grow for bone to grow, for bone to remodel, this is a really strong signal in a very short time, and it's really supported by continued and important improvement in bone mineral density. So again, we're seeing patients laying down new bone, but importantly for these patients, better and stronger bone. Looking a little more closely at BMD and their corresponding Z-scores here. So just by orientation, time on the x-axis for both graphs, and on the y-axis, looking at mean percent change from baseline in lumbar spine BMD, and then its corresponding Z-score on the right.
20 ml per kg patients shown in the solid black line, the dashed line denoting those patients treated with 40 ml per kg. So this on the left is really compelling improvement in bone mineral density. You could argue there's a little bit of difference between these two dosing groups, but that really is driven by a slight imbalance in sex and age, particularly with a few more adult patients enrolled in the 20 ml per kg cohort. And as we'll see in the next slide, the younger you are, the younger you start treatment, the more potential for faster and better improvement in bone mineral density. Transferring this data to a Z-score, and looking at the changes in standard deviations, you see here absolutely no difference between these two dosing groups.
Because of the similarity in results here and the similarity we see across all endpoints, going forward, we're really going to be looking at these 24 patients as a single cohort. We did stratify the phase II part of this study by age, so separating patients from age five-12, 12-18, and then looking at adults from 8-26. I think it follows when you think about the pediatric patients who are growing as well as remodeling, as opposed to adults who have obviously stopped growing and really just focusing on remodeling bone, that there would be the potential for better results in children. What I don't, which I can't say we necessarily would, expected was this strong of a difference and this compelling of a result in these patients between five and 12 years of age.
You know, and seeing a Z-score of positive 0.1, 0.2 over a standard deviation and of improvement is really compelling. So a little more detail on that 67% reduction in annualized fracture rate. So we're looking at fractures in two ways here. So, when excluding fingers, toes, face, and skull, and we're looking at the data in that way, because with conversations with the FDA, that is the preferred way for us to look at this as a primary endpoint for our Phase III. For these 24 patients, in the two years prior to initiating treatment, they'd had a median annualized fracture rate of 0.72 or almost one fracture per patient per year.
Including fractures in fingers, toes, face, and skull, which I would argue are very important, and I think all people fracturing fingers, toes, and face, and skull would also argue important. That does go up to one fracture per patient per year. After a mean follow-up of nine months, that annualized fracture rate comes down to zero. Now, again, this is after just following patients to at least six months. Obviously, we'll continue to treat these patients, we'll continue to follow these patients, and while you can't arguably do better than an annualized fracture rate of zero, we do have a few patients, and we'll talk about them a little bit later with our physicians at ASBMR, but they are feeling better. They're feeling stronger, so they're doing things they've never done before. We have patients who are playing sports.
We're seeing patients doing a lot more, taking more risk, and a few of them have had a few fractures. So with continued treatment, we do expect these patients to also have improvement in their annualized fracture rate. So looking at a little more detail in these patients. So looking at the graph on the left, so these are our 20 out of 24 patients who have not experienced a fracture since starting treatment with Setrusumab. You can see them coming in with their own annualized fracture rate, and you see variability there. With patients one, three, and four included in this trial, you are gonna see some variability here, with patients fracturing quite frequently, and again, some of these patients fracturing more on an annual basis, but all of them coming down to an annualized fracture rate of zero.
Looking in a little more detail on these four patients who had five unique episodes that contributed to fracture. All but one of these events, patient A, B, and C, were really doing types of activities that could result in fractures in people without osteogenesis imperfecta. And as a person without osteogenesis imperfecta, I can tell you, tripping, falling in an outstretched hand can break a wrist, which is exactly what I did. Important outlier here was a patient bending over in bed and fracturing. That is a type of fragility fracture we do see very frequently. These are the types of fractures we're seeing in that two years prior to entering into study. What's really important to note here is that this is only after 1.1 month of treatment.
So again, very early on in treatment, the drug hasn't had the time to really lay down that new, stronger, better bone. So with continued follow-up, we do expect these four patients also to have improvement in their fracture rate. So again, it's important to do this analysis. We're following these patients over time. While we're doing this, these patients are out there living life, and while we're living life, things happen. So what you're seeing here on the left is a car accident. This car in the lighter blue on the right was driven by a 16-year-old male enrolled in this study. He walked away from this, both cars were totaled, not only without any fractures, but completely unscathed. And with that type of force, that type of impact, you would absolutely expect these patients to be fracturing.
Very similar here with this case, this is a 14-year-old female who fell down a flight of stairs at home. She landed first on what you're seeing is her left knee. The parents were absolutely convinced she was fractured and took her for X-rays immediately. She was left with this arguably nasty bruise, but absolutely no fractures, and that's something the parents said would have always resulted in at least one fracture in the past. Another really compelling story here. So this is a child with type IV osteogenesis imperfecta, and they typically are more severe than your type I patients. So you see here on the left, this young man in a wheelchair, really needing wheelchairs and walkers for mobility at home. After four years of treatment, the parents are saying his gait improved, he felt and acted much stronger.
Here we are at 17 months of treatment, giving us the thumbs up. He is no longer using any type of assist device to move around, and the parents say when he's out playing on the playground with his friends, they cannot distinguish him by his gait, by his level of activity, and he's able to play freely with, with, with his friends. Looking at safety, no treatment-related serious adverse events. We have not had any patients discontinued, and no drug-related hypersensitivity reactions. This is an infused product, so we have seen some infusion-related events, and looking here at this list, this is really the typical signs and symptoms you would expect to see in this patient population receiving an IV treatment. Reminder about the phase III part of the study.
Again, with a seamless II-III design, we were able to look at that safety, select a dose from that phase II part, and move into the phase III part of the study. We are very actively enrolling here and looking to enroll approximately 195 patients, again, between five and 26 years of age, with type I, III, and IV osteogenesis imperfecta. They will be randomized in a 2-1 ratio to receive Setrusumab or placebo, and our primary endpoint will be the annualized fracture rate, excluding fingers, toes, face, and skull. So again, this 67% reduction after at least six months of treatment is really compelling in these 24 patients. It also is really changing, I think, the way all of us, and I think we're hearing a lot of talk coming out of ASBMR, about the way we think about osteogenesis imperfecta.
It is a disorder of collagen, and a lot of focus have previously been done on really trying to directly correct that underlying defect in collagen. What we're seeing here with Setrusumab is you can lay down new bone, stronger bone, and offer better protection against fractures without having to correct that underlying defect directly. Also importantly, with this new data in pediatric patients, we're able to look at the way we originally powered our phase III part of this study. Available to us when we originally powered that study was data coming out of ASTEROID. That was a study of Setrusumab in adults done by Mereo, and then the natural history study that was available.
Now, looking at this pediatric data, looking at more natural history, understanding that children are fracturing at a higher rate, and also understanding that parents are telling us that they do not bring their children to medical attention every time they fracture. They have more than enough splints, devices at home, where they can take care a lot of this without having X-rays and documenting this fracture. So we really think this new information potentially opens up a path for an early win here. If we can, you know, quickly enroll this study, the study is overpowered with our original assumptions, then again, really giving us a pathway to win here. We'll now turn it over to Heather. She's the physician lead working on Setrusumab at Ultragenyx, and she'll be sitting down with two of our key PIs in Vancouver.
Thank you very much, Eric. Pleased to join you. I'm here in Vancouver, British Columbia, at the American Society of Bone and Mineral Research Annual Meeting. I'm here with two leaders in the field of treating pediatric patients with metabolic bone diseases. I have Dr. Tom Carpenter, Professor of Pediatrics and Orthopedics at Yale School of Medicine, and Dr. Gary Gottesman, Professor of Pediatrics and Medicine at Washington University in St. Louis. So Dr. Carpenter and Dr. Gottesman, thanks for joining us this morning. Eric just presented the phase II data that you heard on Saturday at the conference. Can you tell me, what's your key takeaway from this data?
This was very striking to me. You know, bone and bone diseases usually take a long period of time to deal with. Bone is a very slow turnover tissue and takes a long time to see results. And here we are at in an early data cut point, and there's a pretty striking increase in the bone density, which I think we can draw from that. The clinical consequences may be less fractures, and then we've got that data on top of it. So I was very impressed at the rapidity of the response.
Yeah, I would agree that the bone mineral density findings are something that was quite remarkable at a rate that I haven't typically seen with bisphosphonate therapy. So, hopefully, the new bone accrual will really reduce the number of fractures.
It's great to hear. Dr. Carpenter, you have a nice way of describing how the increase in bone mineral density makes an impact in patients with OI. Can you tell us about that?
Yeah, I think there's multiple factors here, but the geometry of the bone is a very important feature of the mechanical strength of the bone. One of the features of this medication in the animal studies of the drug is it has the property of laying down bone in a manner that, say, in a long bone, you increase the diameter of that bone due to a process called periosteal apposition. You think you're taking a walk through the woods, and you pick up a small twig, and it's easy to snap it. Then you, a few steps later, see a slightly larger branch that's got maybe twice the diameter.
It's a little bit harder to snap, and there is a mathematical formula that provides you the power to calculate that increase in strength, and it's to the fourth power, I believe. So there's a tremendous advantage to having a larger diameter bone. And I think the aspect of that periosteal accrual is part of what we're seeing happen here, and it's happening at a pace that, y ou know, and I can't say that's the only thing going on, but I think that's probably a major factor in terms of the superiority of what we think we're seeing with this study compared to bisphosphonates.
Anything to add, Dr. Gottesman, of how the increase in how Setrusumab may be impacting OI, the increase in bone mineral density?
Well, I have seen no fragility fractures in the patients I've enrolled in the study. And, you know, years ago, I can remember a 10-year-old boy who decided he wanted to go to a friend's soccer game, was simply standing on the sidelines. The ball was kicked and went out of bounds, hit him in his leg, and broke his femur. So, you know, just normal activities that kids would like to participate in but have OI and have to avoid those activities. I think with this therapy, we may enable them to participate in more normal kids' activities.
That would be amazing. Yeah, it sounds like he was there wanting to participate, and to the ability to avoid fractures like that could make a big difference.
You know, one of the things that comes up is, as, as we take care of these families, we've traditionally told them, "You know, you, you have to limit what your kid can do, or else they're gonna fracture a lot." And , some of the patients that I've seen on this, in this relatively short timeframe, I should mention that the boy in the wheelchair shown earlier, that, that wasn't four years of therapy, that was four months of therapy.
And what started to happen then is he, he started walking with more of a spring in his step. He started doing things. He began to not deal with a walker, and now he's, you know, a year and a half out almost, and h is father is telling me: "Yeah, he's playing at these, going to play at the playground with the other kids for the first time, and we're panicked because, you know, we've been taught we can't let him do these things." So we're seeing that part of it come through, and he's not fracturing. So I think it's that's pretty remarkable.
I have a teenager who was fracturing left and right. Literally, he fractured one elbow one year before starting on therapy. Then, unfortunately, he's a bit clumsy, fell, and fractured his other elbow the next year. He's been on therapy, I think now 13 months. He's a competitive swimmer, and he's finally back in the pool, and his parents and this young boy both all say that he's much stronger than he has been because he hasn't been dealing with fractures and forced to be inactive.
That's great to hear. That's so, this your patient, who's a competitive swimmer, was on Setrusumab treatment as well and was able to get back in the pool?
Yes. He started, he was the second patient I enrolled, about, I think, 13 months ago.
Okay. Wow! And Dr. Carpenter, I think the boy who was in the wheelchair and the walker, and now hardly ever, if ever, uses the assisted devices. It sounds like he had a clinical story as well, where he had an injury that didn't result in any fractures.
Yes, that's, that's right. I'd say about four or five months. Well , I'll even back up a little bit. About three months into treatment, we could just see by exam something was happening. And, and this was, you know, blinded study, but we kinda knew he was, something was different, so we highly suspected he was getting the drug. And, and, you know, his blinded period has ended because of the end of the dose-finding phase of this, and certainly, he, he was.
But I'd say about five or six months into the study, in the wintertime, they were at a restaurant, and there was a lady mopping the floor after they'd finished eating, a hard cement floor, and that kid, you know, he started to run out of the place because he's feeling more active, and boom, falls on the hard cement floor, and the parents go, "Oh, here we go." This is a situation that they said prior to the participation in this trial, this was a definite fracture for him. And so they were worried, took him for evaluation, didn't fracture, and they were stunned because the trauma was substantial, and it was comparable to what it created fractures previously.
You brought up being blinded to the dose group. So the study started as a placebo-controlled that was later removed. So all patients on the study were receiving Setrusumab, either 20 ml or 40 ml per kg. Did you notice any differences that may have suggested patients were on one dose or the other?
No, I don't know. You know, I know in his case that he was, I've been told later that he had been randomized to the lower dose, and his outcome was so good. I really don't know what the others were on, so I can't compare, but I could clearly tell. I did guess correctly of the three early patients we had, that the two that were on drug, and I couldn't have commented on the dose difference between them versus the one that was on placebo. The one that was on placebo, we suspected that as well and were correct.
Yeah, and I didn't have any way of distinguishing the kids that were on the 20 versus the 40 dose.
So you both have a long history of working with patients with OI. Dr. Gottesman, how do you think this drug may be different from the current treatment and approach?
Well, right now, we're really restricted to using bisphosphonates in an off-label manner. None of the bisphosphonates were ever approved for use in pediatrics. They carry some adverse effects. The oral drugs can injure the GI tract. The IV drugs can give you an acute phase reaction, where you feel like you've got the flu, muscle aches and pains. Can also sometimes rarely affect the eye. So having a drug that's actually been trialed in young kids and young adults that is shown to help accrue new bone. The bisphosphonates don't really help you make new bone. They just keep you from breaking down the bone you have, basically. You still make a little new bone, but not in the manner that we do with this drug. So here you get new bone and probably better bone with better connectivity.
The bone ends up a bit stronger.
It sounds like there's still unmet medical need, even in patients who are treated with what's currently available.
Oh, absolutely. That, you know, there are many parents that are afraid of the bisphosphonates and don't opt to put the kids on therapy. And in fact, in the literature, some of the recommendations are to wait until somebody's had two vertebral fractures of at least 50% loss of height before you start the therapy. And so if we have a drug that's proven safe and effective, you might not have to wait to start. You would hopefully prevent the fractures in the first place. We would never take somebody who had extremely high blood pressure and wait till they have a stroke before treating them. We would treat the blood pressure problem and then hopefully prevent the stroke. So, I'd like to think we could do the same for OI.
Yeah. You know, it's like so much in pediatrics, we co-opted something that was designed for other purposes in adults because it's out there, and it's never been, you know, studied in a way that you get a direct indication for the childhood disease, that we just use that. I agree, I don't treat everybody with bisphosphonates. I wait for the signals. You know, and before bisphosphonates, it was, you know, magic. The vitamin D, the growth hormone, none of that stuff worked at all. The bisphosphonates have made some difference. But it hasn't, you know, corrected the situation, and we've got a fair amount of residual disease, even with that as what by default has become kind of the standard, even without approvals and so forth.
The bisphosphonates also, if they're overused, can lead to more brittle and fragile bones and bones that don't heal. So I think there's little risk of that with Setrusumab.
You've talked about treating a pediatric population. We have a study that wasn't talked about today, COSMIC, in children starting at age two. What do you think the benefits will be of treating the youngest patients and starting treatment early?
Well, I'm very excited about this one because I think there's so much of the skeleton that is an accrual and chronic cumulative physiology, so that if you can make the differences early and continue, then you prevent some of the early fractures that lead to the subsequent deformity that makes this the cumulative progressive deforming disease that it is. So the early window is really critical, and I'm quite excited, you know, about that age group. I think that's potentially, in the long haul, gonna have longer, you know, better outcomes.
Yeah, I would agree that the earlier fractures occur, I think the more problematic they are for the child as they grow.
Sounds like if we could stop fractures early, we could really change the course of the disease with that cycle that comes after it, of keeping kids out of activities, keeping them from downstream effects.
Right. You think of an early fracture, then you think of it perhaps heals at the wrong angle, then you have to add the hardware. The hardware itself creates subsequent fractures. So, you know, you've got a situation where you can prevent that at the beginning, the course is gonna be much more normal.
Yeah, and actually applying the hardware from the orthopedic side is much more difficult in the smaller child where they don't have the same kind of expandable rods and things that grow with the tiny kids. So if we can prevent the fractures early on, I think all the kids will be better off.
Tell me, what's participating in this study meant for your patients' families?
Well, they have to come a lot to the treatment, so been a lot of car time. But, they're very grateful to us for being asked to participate, and I think that's really the bottom line. The families are, every, you know, and again, these are the ones that I guessed correctly were not on placebo, have repetitively told me how grateful they are to have been invited to participate.
I think the families are thrilled to have an opportunity to get their children on a drug that may help and appears to help. But I also think they are participating because they wanna help others, and they understand the role of participating in these clinical trials, and I think that's important to them, too.
You know, I have a teenager, and the parents don't, y ou know, they wanna give him his own agency. And so we presented what the study was about to the family and to him, and they backed off. And this kid wanted to do that for the reason you're saying, that he says: "This is a chance for me to help others that have what I have." And I think that that was coming from the kid really tells you their sense of the community, of the people that have this disorder.
Yeah, absolutely.
That's amazing. That's great to give the child a voice as well and being able to participate in the discussion. I understand one of your families has even talked with another family on the study when they wanted to hear from a parent's perspective about participating, was able to.
Yeah, after getting the appropriate approvals, a family on the fence listened to another, and there was sufficient positive experience with it that those folks have just become two children and just become eligible participants. We haven't done the baseline study yet, but they meet all the criteria and have gone through the screening, so.
I've had parents who were on the fence or afraid of the bisphosphonates, who, when they heard about how Setrusumab worked, they were much more willing to participate.
Any other takeaways you'd like to add from the data or your clinical experience of treating patients on Setrusumab now at least six months, and in some cases, Dr. Carpenter, I believe your patient's been on 16 months, 17 months?
17 months trip is this coming Thursday. Things are going well. The kid is, according to the family, he's mixing in with the kids, and it just warms up the parents so much to see their child for the first time not being restricted in the playground. And although they have a lot of trepidation, they're doing quite well with it. You know, it's still early in this trial, and I think we wanna see everything continue in the direction it's going, but we couldn't have a better signal, both from the data and from the patient experiences of, you know, any medication that we've experienced with this disorder.
I would say one big takeaway is just how well tolerated Setrusumab appears to be. I haven't seen a few, you know, injection site reactions, but other than that, a little bit of fatigue, maybe after getting the infusion, an occasional headache, but nothing that would cause any of these families to decide to leave the trial.
An injection site reaction, like where the infusion went in? You just.
Yeah, where the needle was inserted. It's not unusual with an antibody to get a localized reaction, but it's usually gone, you know, within a few hours after the infusion.
I've had one child get a little flush during infusion, goes away when it's over. Have a little headache during the infusion goes away, but nobody with anything at a level that would push them, and nobody's even, you know, raised the issue of dropping out because of the infusion issues.
Yeah.
Well, thank you so much for the engaging discussion. It is just so heartwarming to hear these stories and to see the photo of a child who started the study in a wheelchair and is now, you know, hearing stories about running around at a restaurant, playing on the playground, it being difficult to tell the difference from him and another child. A competitive swimmer who's able to get back into the pool. This is just really amazing to hear. Thank you so much for sharing, and I think we're all looking forward to ongoing your participation in the clinical trial and enrolling patients, and we can see how these patients continue to do. Now I'm gonna turn it back to Eric Crombez to go through the Angelman data. Thank you.
Well, I'm swapping out for Eric this time. Well, thank you, Heather, Dr. Carpenter, Dr. Gottesman, for their discussion. We thought that having PIs talk about what was happening in the trial would be helpful to all of you. I'm gonna go through the Angelman data. We'll also have a panel discussion with Dr. Olugemo and Dr. Berry-Kravis after that, and then we'll have a Q&A session. So all of you that are thinking about questions, so tally up your questions, and we'll get to them. So I'm gonna talk about the Angelman program. Obviously, well, not, m aybe there's not that much interest in it here. Well, maybe not. Maybe there is. It's been an exciting program for me.
I mean, Angelman syndrome is one of those diseases we learn about in as medical geneticists, but you, I always thought this was gonna be too hard a disease to treat. It's one of those developmental delay things with the complex genetics. There's no way to treat this, but yet, yet someone figured out a way. Dr. Dindot and others, Dr. Beaudet, figured out a way, and we're gonna show you data that's working, and we feel very excited about Angelman and the ability to GTX-102 to change the future for Angelman syndrome. So obviously, investigational drug, and this is open label interim data, but, I think you'll see very compelling. So GTX-102 for Angelman is an antisense oligonucleotide for this developmental disorder. There's 60,000 patients approximately. We're gonna be talking today about the extension cohorts.
There's also expansion cohorts, where we're picked a dose and a regimen that we're expanding patients. We've pushed that out till we can have at least 20 patient data later next year. So today is about the extension data, those that were on dose titration and put on extension. That will be the data focus of the day. One thing about GTX-102, it's very important to recognize, is that it targets a very unique part of the locus where the antisense message is created, the very five prime end of that antisense message. This was the tour de force of molecular genetics that Dr. Dindot published recently. I suggest you go into that. If you can read that paper and really understand everything in there, I'll be very impressed. It is very complicated, and I'm a medical geneticist, but it is complicated.
But what he figured out is that if you attack the five prime end of the message, right near the beginning with an ASO, you will clip the transcription of the message as well as destroy the messages, that it's far more potent at the five prime end, and that region is beyond the Ionis-Roche patented region. So it's our own select region. It's the only reason we got into the program. We got into the program because in order to compete with Roche and Biogen Ionis, we had to have an edge, and I really believe that one great scientist can be better than 10,000 employees at a big pharma. And Dr. Dindot figured out something that no one else knew. That's what GTX-102 is. And we've shown you it's very potent on nonhuman primates.
It's why we said we can be the best drug because of this insight and the targeting of the drug. That puts us in position to be the leading program, and I think from what we're gonna show you today, I think we are the leading program and one that can make it to approval. Today, I'm gonna talk to you about multiple domains are improving, both loading and maintenance phase in these patients, and we're gonna compare to natural history, which was a request where we have natural history data. We'll show that these clinical changes are associated with quantitative changes in the EEG, showing that the, that basically the objective neurophysiology is reflecting what you're seeing in the clinical.
Then we'll evaluate for clinical meaningful changes using a multi-domain responder, as well as looking at early developmental gains, the things that parents look for in your child. If you have a kid, you think of when they first walk, when they first talk, those are the things. And we'll look at those emerging developmental gains reported by caregivers also as a way of assessing clinical meaningfulness. In the end, we'll have a panel, Dr. Ologemo and Dr. Berry-Kravis, who will look at some video examples as well. So the data that we're gonna focus on today is cognition, sleep, perceptive, communication, behavior, and gross motor. And three of them are from the Bayley, two of them are the Angelman's, or three Angelman Severity Assessments. The Bayley is a well-described detail. There's a lot of natural history data, and that's what we'll use in natural history comparisons.
The Angelman Severity Assessments are Angelman-specific questions, and I'll explain a little bit further just a second. But this combination is the ones we focused on. There are others who have a similar pattern result, but we, we decided to focus on these for this particular presentation. The Angelman severity assessment is something I think is endpoints are designed specifically for Angelman. Basically, in these Angelman severity assessment rating scales, there are 68 questions that are defined that, that characterize some aspect of the endpoint, and the doctor is scoring on those 68 questions, and that together then leads to an ASA rating somewhere on this scale. Most of the patients are between three and six, mild to severely impaired. And a one point change here represents going from, let's say, markedly to moderately or moderately to mild, is intrinsically clinically meaningful. It's a big move, right?
There's only a six-point scale. Most people are in the middle. So I think it's we like this scale because it's really designed for Angelman. It captures things that are important in Angelman for some of the endpoints that we're gonna talk about today. So the interim data will be the cohorts four through seven, which were enrolled outside the U.S., and their loading doses in the range. Most of the patients were in the three to 3.3-7.5 range for most of the doses, and the maintenance was 10-14. Many of the patients started lower and were titrating through the maintenance phase. And 11 patients have a year of therapy or longer. So we'll talk through a whole set of data.
We should add right now, just as a preview, there are no lower extremity weakness other than the last one we talked about early in the year. All right, just to remind you about the dosing schematic and the time evaluations. There's four monthly doses at the beginning, and then they go into every three month dosing. We previously showed you day 128 data for some of these patients. We're gonna take, the loading phase, we're gonna take all the way through day 254, which is where we think the effect of loading is continuing to have impact, and that'll give you what we call loading phase. And after that, we'll look at beyond that for a maintenance phase of treatment. Now, the natural history data for comparison is published natural history data. The references are below.
There are 64 patients who have the same deletion type at Angelman syndrome and the same age range, 4-17. We took the data out that matches within the trial, so they match from both genotype as well as age. They had to have at least two consecutive assessments to show the change in order to be incorporated in this analysis. The Bayley-4 is really the place where we have that data, but that will help us with at least three endpoints that we can look at. Here's the cognition score by Bayley. Now, we didn't show you a cognition score before. The cognition scale here shows that improvement at day 128, but by day 254, you can see they've crossed the 5-point scale, which is a statistically significant.
So that means the change is greater than a statistically significant level and achieving about near eight points. When you look at the natural history at day 254, which we interpolate between zero and 365, you can see maybe, maybe one point change, right? So a substantial more change compared to natural history. Now, if you take that cognition during that period of time and look at the EEG, we can show statistically significant reduction in delta power correlating at that time. And if you draw a correlation between the change in the Bayley Cognition Score and the change in the delta power, which is a neurophysiologic measure of Angelman we see in Angelman, you can see a nice correlation between the improvement in their cognition and the improvement in the EEG.
This just gives you what I would call the objective underpinning data of neurophysiologic change from the antisense oligonucleotide that is translating into an effect on cognition. When we look at sleep, we see a very significant improvement in sleep. In fact, sleep change tends to happen very quickly for many patients, even within one dose. But you can see they achieve a full point on average by day 254 in these patients. And if you look at EEG now at sleep spindle, which is a sign of normalization of sleep function, you can see a significant improvement in sleep spindling by day 254, in consequence with the, you know, in coincidence with the sleep improvement.
This shows that the neurophysiology is also changing, that relates to spindling and sleep, and I think it's just another sign of the objective correlation between the improvement we're seeing in sleep. We look at receptive communication. We can see initial of variable improvement by day 128, but then, it the mean exceeding the statistically significant level of six at day 254. And when you compare that to what you see in the natural history for the same type of patient, it's in the one to two point range, so a significant improvement above what natural history would be expected at that point. If you look at behavior by the Angelman Severity Assessment, and the Angelman Severity Assessment really is focusing in on the ability of the child to focus, their hyperexcitability, maladaptive behavior, transitions, impulsivity.
So the kids are hyperactive and reactive in what they do, and you can see the significant improvement in behavior scores, particularly for this instrument. So that's sort of the early phase, loading phase. Now, the question is, what happens when you look at these kids over the longer haul? And we'll go into the maintenance phase. During this period, the patients are titrating up in their dose, and we're now looking over up to day 500. So what about cognition? I just showed you. I showed you at day 254, they crossed the threshold around eight, and you can see between day 254 and 506, the patients continue to gain ground as the titration is occurring, achieving now double-digit levels of improvement.
Whereas if you look at the natural history in the cognition, they are maybe at two points, whereas now we're at maybe almost 15 points improvement, right? So a dramatic difference from natural history and showing this consistent pattern over time. If we look at the cognition, and now we happen to do this at day 422, when the EEG was done, you can see again, a very strong correlation between the Bayley Cognition Score and the delta power, consistent, showing the consistent neurophysiology as an objective measure, reflecting what we're seeing in cognition again. We look at receptive communication, you can see the rise at 254, and it continued beyond that as well. Again, near 8 points change, which is above the statistically significant level of change and compared to a couple of points at day 506 in natural history.
So again, another endpoint, a third endpoint showing substantial improvement above natural history. Look at the gross motor now, which we didn't show in the shorter term. You can see it gaining ground throughout and continuing to accelerate toward the end, now crossing the five point statistically significant threshold at day 506 in these patients. And you can see, you would expect maybe a point or so if you look at day 506 in the natural history. Again, another endpoint showing substantial improvement beyond natural history. If you look at the sleep by the Angelman Severity Assessment, you can see a significant improvement in sleep over the 506. It's pretty stable. It comes very quickly and stays very stable.
If you were to look at the patients who had severe sleep disturbance, which is minus a four score or higher, they actually have almost a two point change, 1.75-point change in there. So among patients with severe sleep problems, the severity change is dramatic, going from, let's say, severe to mild in some of these kids. So it's, for a family, sleep, by the way, is a dramatic problem if your kid's up all night for years and you're up and doing what you have to do. We'll hear more about that in this section later. Behavior, again, over the long haul, over 506, steady improvement in behavior scores over time, past the 254-point, continuing to improve. I think you can see a steady pattern here.
Every single endpoint is moving better and better over time, including ones we haven't shown you. Overall, Angelman's, as you might expect, also showing steady improvement over this timeframe in these kids on longer-term treatment. So with that, we've shown you quantitative evidence that the patients are improving in multiple domains. They're improving during the load period as well as during maintenance period, continuous improvement. And they are by the magnitude exceed the threshold for what's considered statistically significant difference from the Bayley and so far exceed what you see with natural history. Now, to understand and look at this at the more clinical meaningful side, we are gonna look at a couple of different ways at the data. First, I will do, and then we'll have Dr. Elgammal do the other part.
One idea we brought forth is what we call the Multi-Domain Responder Index, and what you do in this situation, you look at these quantitative endpoints and you score what's the minimally important difference, what would be considered a clinically important change in that quantitative, and then score patients on that. So you pick four-six clinical domains. We'll show you five domain choices: behavior, sleep, behavior, receptive, growth, and cognition, you score, then if they cross the minimally important difference, you give them a plus one. If they decline, you give them a minus one. If they don't change that much, you, you call it a zero. That doesn't mean that small change doesn't matter. What we're saying is we're going to tabulate the big wins or big losses. That's what we're looking for, to capture clinical meaningfulness with that threshold.
Then we count up how many changes are positive, negative, and you get kind of a net change per person. Because we count only significant changes, that means the results that are positive are intrinsically determined to be clinically meaningful based on the thresholds that have been set. And by combining multiple domains of data, it allows you to capture, in a sense, the totality of the data in this kid. How's this kid doing over five domains? How does that add up? We think it's a powerful way to do this work, and Dr. Tandon and myself have written a paper on the topic. It's part of what we do in leading the future of rare disease medicine. We think it's for neurology diseases, complex ones, we think this is a very powerful method.
So we ran the mDRI here, and the green is the, the domains that show improvement, and we show the scores there, and then a declined score is purple. You can see on the left are the 5 domains for the patient scored here. On the, on the right column are the total net responses for each patient. What you can see there is a lot of green, right? That means there's a lot of domains in each patient that are coming up positive. You can look across the rows to look at that. Many patients have multiple domains of improvement, but between one, five domains in every patient. If you do a statistical test of this change from baseline, the p-value is 0.001. It's very powerful because you're capturing movement in multiple domains like this. It's a very powerful assessment.
The mean total net response, about two plus. Some patients have as many as five domains. You can see three patients that have five domains improvement, right? That tells you how dramatic it is, and certainly some that have fewer, it wouldn't be surprising for a complex neurologic disease. But what you can see here is a clinically meaningful change across the board in domains in many patients. So what we've shown you so far is that we have improvements far exceeding natural history, and we also have improvements in the ASA, in sleep and behavior as well. We have supportive data from EEG, and we can show you with the mDRI that these are clinically meaningful changes, based on established and minimally important differences. So that, I think, puts us in a good position to understand what we have.
Let me talk about safety overall. This includes safety now for the expansion cohorts as well as the extension cohorts. So it's all safety, 58 patients so far. No patient with lower extremity weakness since the last one we described. We have no unexpected adverse events or safety events. Patients have received up to 11 doses now of GTX-102, and you can see the most common events are actually anesthesia-related. They have issues around anesthesia, and that would be the biggest issue, but most of the other things are what we call incidental. So we feel very good about safety profile so far with as many as 11 doses. So where are we at for next steps? We've enrolled more than 30 patients in cohorts A and E, the expansion cohorts, and we expect to have. There's 25 sites active in eight countries.
The idea here is to set up as many phase II sites as we could, so that they can be tested, developed, and become the phase III sites. This is part of a technique to set up the phase III sites, so they all have run, done the treatment, done the measures, and now they're primed and ready. That's why we have so many. We did it purposely to help set up what would be a rapid entry into phase III. Obviously, no lower extremity weaknesses, but with the number of patients enrolled, we're confident we should be, have 20 patients at least of data, that have at least six months of data in first half of 2024. That will be the next major update. These patients were all loaded the same way rather than titrated, and then in maintenance the same way.
So this is now taking what we've learned from dosing and maintenance and putting them into a program that help us show what phase III looks like. With that data, we'll analyze it, predict how phase III will be, and then finalize our plans with the FDA. We are expecting and have communicated with FDA, and they are agreeable to meet with them beforehand just to talk through endpoints, just as they invited us to Type A meeting to talk about the endpoints. So they're definitely leaning forward to the next step with us. They know the endpoints are complicated. We're agreed to a meeting, we're gonna be talking about that, and we'll kinda gain understanding of how to come to a final conclusion on endpoints.
We'll bring them then when we get the phase II data, come back with a final plan at an end of phase II meeting. With their agreement, then take off, and our expectation is to be in a phase III study this coming year. So that's the story from the data so far. I'm gonna bring up Dr. Ologemo and Dr. Berry-Kravis now. They're gonna talk through some of those emerging clinical findings and patient experiences, as well as some videos. Thank you, Dr. Ologemo and Dr. Berry-Kravis. I think, who's been working with this program for a long time, and we appreciate all her diligence. She is the most incredible investigator in terms of getting work done. We need to clone her, but thank you very much.
Thank you, Emil. Good morning, everyone. I'm Kemi Olugemo. I'm the study physician for the GTX-102 program, and I'm joined here with Dr. Elizabeth Berry-Kravis, who is Professor of Pediatrics and Neurological Sciences at the Rush University Medical Center. So Liz, you've been a PI for this program right from the beginning, right? So you have a lot of history here, and you have an extensive background treating patients, not just with Angelman syndrome, but with other pediatric neurodevelopmental disorders. You know, we thought it would be great to really get your firsthand experience in the trial and talking with the families. We thought that we would start with the original patients who entered the trial at dose escalation cohorts.
These were relatively high doses compared to what we're using right now. So those patients were dosed, paused because of a safety event, and then redosed. So here, on this table, we have three of those patients, and you know, what is immediately striking is that these patients gained first skills that they had never attained before starting the trial. They are organized by domains, and these are domains that are really important and pertinent to the presentation of Angelman syndrome, but also important to families and have been published in the conceptual model of Angelman syndrome. So we know that these are relevant, and also, they are part of a lot of the outcome measures that we're using in the current trial. So these patients have gained new skills in multiple domains.
Actually, before I talk about the specific domains, I wanted to point out that these skills were lost, and all the skills were regained. To lose a skill after a couple of years and regain the skill, it's likely not due to normal development. It's a drug effect, so we think that this is real. We'll start by communication. You know, we have the ability to respond to their name, follow a one-step command, or follow a complex command, two-step or complex command. What do you think the impact of being able to gain this type of first receptive communication skill is on a family?
So, that's, that's just a really important step. Most of the time, Angelman patients really just don't respond. Like, they do what they wanna do, and they wander around the house, and you call them, and for instance, one of our patients didn't even respond to his name before he went in the study. And so when he would be doing something unsafe, and they would yell his name, he just didn't respond. He kept doing the unsafe thing. Whereas after treatment, he began to respond to his name. He would stop, he would look, and then the family had a few seconds to grab him before he put his finger into the outlet or, you know, something like that, or before he touched a hot stove. And then following multiple-step directions means that the patient can be more independent.
You don't have to do everything for them. You can say, "Go get your shoes and bring them to me," and then they can carry that direction out. So really important for them to be able to actually respond to what other people are saying to them.
Well, thank you for that. So what about the effect of receptive communication on learning, the ability? Can you talk a little bit more about being able to understand a command and how that impacts the development of other skills that are required that you see here on the table?
Right. I mean, you do have to understand what you're being asked to do in order to learn anything. So we had a number of the patients who were actually in Zoom school at the time of COVID and when they were first in the study in 2020, and they didn't pay any attention to school at all. And then a couple of them were actually paying attention to school on the monitor, and then later on, when they went back to school, they were able to actually sit in the classroom and focus and do what the class is doing, rather than just kind of wandering around aimlessly in school, which allows them to take in what's being taught to them.
Essentially, communication is a gateway to other skills being developed, right?
Yes.
Yeah. So, so in terms of expressive communication, here we see first words and multiple words, and, you know, Emil mentioned how, you know, for those of us who have kids, we all remember the first time our, you know, children walked or talked, right? And, and so here we see this happening for Angelman kids. So, you know, what kind of effect has this had on the families?
Well, I think, you know, speech is the biggest deficit in Angelman syndrome. It's kind of the hardest barrier to get over for them to learn. And one of our patients got nine words when first treated in 2020, and even that was very exciting. I remember when they texted me the video of her saying, "Mama," for the first time at a dinner of the whole family, and it, y ou know, you just cry when you see stuff like that. So they're very excited, and she lost all of those words when she came off the drug for two years, which suggests that she didn't just gain those words because of development. It was because she was being treated with the drug.
And then going back on, now on the lower doses, but being treated a little bit longer, she now has 17 words and counting. So, that's, it's very exciting to see even a little bit of language emerging. Those words are really very, you know, important to families.
Yeah, that's pretty impressive for somebody who couldn't say a single word, actually couldn't even, you know, use cosonant sounds prior to starting the drug. I also wanna point out that, you know, even if spoken words aren't there, there are other ways of communication right? Like using a device, that are really important to be able to communicate their, their wants and needs, and have those kinds of improvements been noted as well?
Yeah. We've actually seen those improvements more than words. There are numerous patients who have actually started to use their AAC device. They had a device because they didn't have any language, so everyone, you know, gets a device like that, where they can point to pictures in order to communicate because they don't have words. But many of the Angelman patients will have the device, but they'll just kind of hit it randomly and won't actually use it to communicate, except on occasions. And so many of the patients in the study have been much more consistent about using the device and have actually learned that the device is important to communicate, and if they want something to eat, they'll bring the device to the family and point to what they want, even if they can't say the word.
So that really improves the ability of the family to know what their wants and needs are, which typically, the family just has to guess, you know, why they're unhappy or what they want.
Yeah. Thank you for pointing that out. And we don't have cognition here on, on the slide, but that's clearly a part of learning, learning to be able to use a device. So let's talk about sleep. So we saw the Angelman Severity Assessment. We saw that improving with treatment, and, and we saw an even more dramatic improvement in patients who had a severe problem at baseline. We've also heard that, you know, sleep is one of the very first domains to improve and, and which families see an effect. So, you know, what does it feel like to be able to finally sleep through the night for these families?
Well, you know, some of the patients don't have a big problem with sleep. So we did see mild improvements in those kids, but it wasn't life altering. But for these kids that have, and it's maybe about 30% of the kids with Angelman syndrome, we had one in this initial group. For these kids that don't sleep, period, like, one of the kids, he never slept more than three hours a night for years, from birth, and he enrolled in the trial when he was five. So if you can imagine five years of never having your child sleep more than three hours at night, you can imagine how sleep-deprived the parents are. And this is one of the things that does respond very quickly.
So when we first treated him in 2020, he got one dose before he got the leg weakness side effect, and they called me, like, three weeks later and said, "He's sleeping through the night. Like, we don't know what to do with ourselves because we are getting more sleep than we ever have in the last five years." So, that was an amazing transition, and then he had about four months of sleeping through the night because he never got another dose because of the leg weakness. The family, you know, the, the whole thing deteriorated, and he was back to his two or three hours of sleep, and then when he went back on the lower doses later on, literally within two weeks, he was sleeping through the night again, and it's, it's, it's like a miracle to the family, honestly.
Yeah, and we've heard that for these families, where kids sleep three or few hours and have frequent awakenings, usually one caregiver has to stay in the room with that kid, right?
So being able to sort of take back your time and the implications of, you know, being able to work, being able to accomplish more, seem like they go well beyond just sleeping. Yeah.
Oh, yeah. The family, in this case, like, when he woke up, he was irritable and agitated, and the only way they could get him to calm down would be to take him out in the car and driving him around at night. So one family member was up driving around in the car with the kid all night, basically.
That doesn't sound fun.
No.
Okay, so gross motor. So we've, we have kids who, for the first time, learning to throw and catch a ball, losing the skill, but then regaining, walking upstairs. What's the impact of being able to walk upstairs without somebody helping them? Reciprocal climbing, which, you know, you take for granted, but these kids are so ataxic, and that they can't do that. So what, what's the impact of that, and also reduced falls?
Well, if they can go upstairs on their own, they can get around better. The family member doesn't have to carry them up the stairs, and as the kids get bigger, they are more difficult to carry up the stairs, you can imagine. So being able to be independent with those kinds of motor activities has a big impact on family life. And the falls, the kids are ataxic, and so they, meaning that they're unbalanced, and so they have difficulty with surfaces that are uneven or with like, they won't pay attention to what's on the floor, so they'll trip over something lying on the floor, and then they fall constantly.
So, definitely being able to navigate, to know what's in your surroundings and navigate, and move about, and climb are all things that improve their ability to function day to day.
Function and also safety?
Yeah.
Yes. Okay. So I think we'll move on to the wider cohort. So we first discussed those patients who were originally dosed, paused, and then redosed, and now we have here the same heat map essentially showing new skills that were gained and the entire cohort of patients that Emil just presented. And then you essentially see the same thing. So any green cell is a new skill that was gained. And you can see for all patients here, they have gained new skills, new developmental abilities in multiple domains, some of them all five that we're measuring here. Any comment about this?
Well, this is a lot of new skills, and honestly, for as someone who's seen Angelman patients in clinic for, you know, decades, these patients, after they get to age four or so, which is the younger end of the cohort in these trials, they don't gain skills rapidly. It takes them years to learn a new thing. So the fact that these patients have all learned things in less than or a little over a year and learned multiple things, is more than what you get even with extensive therapy in these patients. Their learning curve is just very flat. So this is pretty impressive for this condition.
Oh, thank you for that. I have to agree. So I think we're gonna move on to the video portion, and just a note that this is, you know, for confidentiality and privacy reasons, we're asking people to refrain from taking any photos or videos during this section. But you know, I like to think of you know, a picture as you know, being able to demonstrate you know, a 1,000 words, and a video even a million, right? So we thought it would be great to you know, for people to be able to see some of these skills that we've talked about to give a clearer picture of what's going on with these children and families. So sorry, I skipped ahead.
So we're gonna go ahead and play the first video. So, the first. Maybe before we start, the first video is a patient who you see eating. You can go ahead and show what you see.
This is her, a month before she went on the drug initially, and you can see the speech therapist is, or the OT is working with her and trying to get her to use the fork. She can't really figure out how to get food on the fork. She doesn't show the motor skills to do that, and often not the cognitive skills to stay focused, and her arm movements are jerky and ataxic.
And then the speech therapist or the OT puts the fork into her hand in different ways to try to get her to use it, and then finally just picks it up on her own, and then has to kind of hold her hand to even help her grab the fork, and then she doesn't really know how to use it, so she puts it down the wrong way. And now this is her after she's received treatment, and you can see she knows what to do with the fork. She's directing it correctly, she's getting the food on it, and this is a smooth movement that's much more coordinated. And this means she can eat on her own at the table, at family meals, and the family doesn't have to sit right next to her and feed her, and everyone can enjoy their meal, eating independently.
So you pointed out multiple, multiple domains here that were, y ou know, we saw in that video. So, fine motor movements, being able to hold a fork properly.
Right.
The cognition piece, being able to understand how to hold it and which end of the fork goes, you know, on the food and what goes on the hand, and then, you know, her coordination was also improved, right? And all these have impacts on the quality of life of the patient and functioning for the family.
Absolutely.
Okay. So, the next one, in the same patient, shows this patient pre and post-drug, walking on a hard surface and then, walking on a soft surface. So she's at the beach with her family. So you'll see again, the pre and post, and I think we can go ahead and play this one now.
Okay, so this is gonna be her walking on a boardwalk, and so you can see her broad base. She keeps her feet wide apart because she's unbalanced, and that's how ataxic people maintain balance, and she kind of has a jerky gait, and she has her arms up in the air because holding the arms up helps her maintain balance. And then she goes out in the sand and doesn't like that 'cause it's hard to walk on, and goes back to the boardwalk. This is her post-treatment, and she's just plowing along on there. You can see her gait is much more normal and much more narrow. And then here's her walking on sand.
Sand is very difficult for patients with Angelman syndrome cause they don't do well with things that are uneven, and then the sand is slippery, so it throws them off balance, and they fall easily. And you can see she kind of walks in fits and starts and has to stop, and then gets forced to turn 'cause she's kind of going off balance and, and then falls relatively frequently. Now, this is her walking on sand post-treatment, and you can see she has a nice, narrow base to her gait, and she's just plowing along through the soft sand. And so this is, she's a little bit older here because this was after she was retreated, and the initial video was before she was treated. But this isn't just because she was older.
She had similar videos of being able to walk on sand quite well, right after the initial treatment. But you can see the difference in that gait with the broad base, you know, kind of trying to maintain support and then the rapid, smooth, narrow gait. And people can't fake that, so that's a real finding.
So, Liz, you're just to clarify, you know, she was older in the post video. When she was younger, did she gain the ability to walk on a hard surface and a soft surface and then lose that and then regain it?
Yes. Her gait was much better, and we watched her, you know, moving through sand very easily after she went on the treatment. Of course, then she developed the leg weakness, and then she couldn't walk at all. But after she recovered, she was walking even better than before she got the leg weakness for a while, and then her gait became worse, and then, b ut not all the way back to baseline. And then when she was retreated, her gait improved and, you know, really has improved dramatically. At this point, it's still improving because she's been on treatment for longer this time, so she's had more time to improve. So even though it's a lower dose, there seems to be a time effect, where over time, you keep gaining and improving the skills.
Yeah. And one thing I don't think I heard you point out, you may have forgotten, was just the speed at which she was walking as well, you know, after being on drug.
Oh, yeah, she's walking much faster. I think now, at this point, there's even starting to run maybe a little bit. So, yeah, the motor skills are ongoing and improving. She can jump on a trampoline now, so really, steady gains, and hopefully we'll continue to see those.
Yeah, we hope so. So, we have one last set of videos for this patient, and this, I think, is really the most impressive because, you know, you'll see this patient on a boogie board, and you'll see her swimming, you know, in a pool and, you know, it takes a lot to be able to learn how to swim. You have to be able to learn how to breathe, you have to coordinate your hand and your leg movements, and Angelman kids have a lot of difficulty with coordination. It requires strength, it requires the cognition to be able to move from one end of the pool to another and be aware of your surroundings. So we'll go ahead and play this video.
Okay, so this first video is something I never thought I would see in an Angelman child. This child is on a boogie board, and you can kind of see her coming in, even though the face is blocked out there. But she's holding on to the boogie board, and the waves are coming over her, and she has the focus to stay on the board and hold on for an extended period of time and maintain balance when the waves come and slide in. And what you don't see is she hops right up off that boogie board and stands up easily in the sand and then takes it back out to the water. So that's amazing. We don't have a pre-video, but this child could not even hold her breath, let alone swim, before she came into the study.
While she was in the initial, a nd what you're seeing here is her swimming across an entire Olympic-sized pool with no floaties or flippers. When she was in the initial phase, when she got treated the first time, she learned how to hold her breath, how to dive down and get a little rock off the bottom of the pool, and then how to swim with swimmies and flippers on. Then she went off treatment, and she lost that ability. She couldn't swim anymore. And then when she went back on treatment, she started out swimming with the swimmies and the flippers, and by the end of the summer, was swimming across an entire Olympic-sized pool. And you have to realize what a huge, important safety thing this is because Angelman children love water. It's an obsession with them.
They want to be in the water. If they can't hold their breath, they will walk into the swimming pool and die happy. So that is not good for anyone. And actually, death by drowning is the number two cause, after seizures, of death in Angelman children. So this is a huge safety improvement that you just saw. Not only that, she can enjoy going out with her other sisters and her family and can boogie board with them. And actually, I have a recent update that she is kneeling on a surfboard and coming in over the waves recently, and that's, like, unheard of for Angelman syndrome.
Looks like we're on our way to Special Olympics here.
That's right.
Okay, so I think this was really nice to see the complement of all the different domains impacted in this one patient, starting from, you know, eating, to be able to walk and then swim. So definitely, you know, would you say that's encouraging?
Oh, yeah.
Okay. So now we have, we have another patient, and that patient has two videos. The first is, a pre and post-video of this patient, eating again, and then the second one is of the patient walking. So let's go ahead and start the first video.
Okay, this is him eating before he was treated, and this is not a selected video. This is what he looks like after every meal. He basically smears food around, throws food, gets a little bit of it in his mouth. If they want him to actually eat anything, they have to feed him. But this is the mess that it looks like. This family describes giving the child a bath after every meal. This is real because when we have these patients in clinic, you know, there's Cheerios and food, fruit snacks and everything all over the place. So that's what eating looks like. It's disorganized and impulsive. Now here he is after treatment, and he's focused. He's thinking about making a motor plan.
He's gonna reach out, get the fork, put it in his mouth, eat the food off the fork, and then give it back. And so that's a much more organized way of eating than what he was doing before. He wasn't able to grab the fork because his hands were too ataxic before he went on the drug. And then here he is. He's got food on his plate, but it's not getting thrown all over the place, and he's gonna focus and get one chip out of the bag and eat it, and then he'll go back in the bag. And he's actually able to just pick his food up off the plate now and eat it, rather than making a giant mess, and the family no longer has to give him a bath after every meal.
This is a substantial improvement in his eating, and we hope to see this continue to improve to the point where he's able to use the utensils independently.
Yeah. Thank you for that. I, I saw improvement in both, limb and truncal ataxia in this patient, ability to focus and motor planning, as you mentioned, and then the fine, finger movement. So again, multiple domains really being impacted in, in one video. So I think the last video we have is of the same child walking, pre and post-drug. Let's go ahead and play that one.
Okay, so here he's gonna be walking before treatment. You can see the broad base again. He needs to do that to maintain support because he's ataxic, and the arm's in the air, you know, kind of flailing around, but trying to maintain support. And then here he is after treatment, where he's actually walking on a moving walkway, and you can see how much more narrow his gait base is. He doesn't need to keep his feet apart to maintain support, and he can stop. Stopping and turning are times when Angelman kids fall. He stops, turns, and walks backward on a moving walkway, which is very impressive for Angelman syndrome, and then he's gonna turn around again and go the other direction.
This is really a big improvement in his stability and his balance, and leads to decreased falls and increased ability for him to ambulate without the family having to take a stroller around. You can see the change in his base after treatment. Again, something that you, there's no placebo effect here. You know, these kids don't even know to have a placebo effect, and this is a real motor finding that we're having.
So very similar to the first patient, where you saw the wide-base gait, ataxic gait become narrower and smoother. Patient, you know, this has implications in terms of the family needing to use, you know, either a walker or, you know, a stroller, like you mentioned, implications on travel, right?
Oh, yeah.
For the families. And then the safety aspect in terms of reduced falls.
Yeah. Yeah, we have families who don't even have to take the stroller on vacation anymore, which is very exciting for them.
Yeah. That's very significant. Okay, so any last words in terms of the totality of the new skills that we've seen, right now?
Yeah, I think what I've seen has been amazing. I mean, frankly, when we first dosed these kids in 2020, it was the middle of the pandemic, and these families were telling me, like, "This drug is working." And it was only, like, a couple of weeks into the first dose or two, and I would be like: You guys are having a giant placebo effect. Send me a video of that because I don't believe it. And then I would get these videos, and I was like: Wow! Because having worked in developmental disabilities forever, we expect changes in development to take a very long time. And this, this, this change in these Angelman kids, although they're not close to normal at this point, but it's, it's very, it's very dramatic. And I can only hope that these changes build over years.
I mean, we have to remember, we're putting an ASO and correcting things genetically in a brain that can't learn as fast as a baby anymore. So the learning may progress over a very long time, and we may have to wait 10 years to really know how much these kids can be different from what's expected. But what we're seeing so far is honestly more dramatic than anything I've seen in a developmental disorder with any treatment before.
Yeah. Thank you for that summary, Liz. And I think, you know, the videos are a nice complement to the objective data that Emil presented to show you the totality of what we're seeing with GTX-102 in this trial. So, again, I just wanna thank you for everything, you know, you, you've done, in the trial, your work in the trial, and, and especially for, you know, treating, treating patients and, and being sort of a guiding light for them. And, of course, you know, thank the patient families who provided these confidential videos and, and all the patients taking part in our trial and those taking part in other trials, because we know how challenging that is, and we are all in for Angelman. So this concludes our section. Thank you.
Okay. Thank you.
It's up to you. You're great. Q&A right? Got it. I'm sorry.
Very good. Thank you, Dr. Ologemo and Dr. Berry-Kravis. So you've now seen the Angelman data, quantitative data, natural history comparison, EEG, clinical need for this, and also videos. Hopefully, that gives you a sense of where we are and why we're confident about the fact we have an excellent drug in the GTX-102, and we're excited about the prospects going forward. So we've given you now talks on the OI data for Setrusumab, showing, I think, transformative effects on bone mineral density and fracture rate, and some of the clinical insights, and then we've given you the Angelman story as well. So we're open the floor now to Q&A. Tazeen, I saw your hand first, so you get the first question.
Thanks, Emil. Good morning, Tazeen Ahmad, Bank of America. So can we back up to the first presentation, maybe for OI? I wanted to just explore the comments that were made by the physicians about parents being, at some points, scared of putting their kids on the bisphosphonates. And do you have a sense of what percent of patients actually don't get bisphosphonates at all? And would they potentially be the ones that could be the first adopters in terms of treatment possibility in a real-world setting? And then, the data that you've shown today was impressive and clearly shows that the earlier you start treatment, the better. How are you thinking about treatment for children as a result versus adults, and what would be the benefit that adults, in particular, could see in addition to bone mineral density?
Yeah. So on the question of bisphosphonates, we've been talking to a lot of people about it. It's, it's rather interesting to see. There's certain doctors have certain take and view. So some are treating everyone, some are treating very few. It's, it's actually highly variable between different doctors. So it's a little hard to say there's a decided number. A lot, a lot of the patients are on bisphosphonates, but I can't tell you a precise number today and honestly, clinic by clinic, we see a lot of variations. What I would say to you is that most of the time, what's happening, if the patient are having a lot of fractures, the bisphosphonate is the one thing they can offer them. But the fact that bisphosphonates, at least in the randomized studies, has been where they've succeeded, two out of five studies have been successful.
There's about a 20% decrease in fractures, so it has some effect, and it has some effect in some patients, but it's, it's the only thing they have to offer. So I would say to you, it's, it's not the majority, but it's a good fraction that are on bisphosphonates, and it's highly variable, depending on the doctor and their view of whether it's helping them or whether it also can potentially bring up risks, as Dr. Gottesman was talking about, which is chronic use of bisphosphonates can actually create more problems in the bone in the long run. I don't think it's gonna determine who wants to be on the drug. I think bisphosphonates will become irrelevant to it. I think the people are gonna look for ways to make bone and whether you're on it or not.
By the way, all the patients essentially in the trial have been on bisphosphonates in the past, or a very large fraction. So we know that it works on top of whatever you've been getting in the past, although they're not on bisphosphonates in the trial. With regard to adults and children, there is no question that children will have a better effect, but I think adults will have an important effect. And certainly, the adults in the ASTEROID study, when we first started working with Mario, were contacting us, wanting to get back on drug. I mean, there was interest in getting back on it. I just think that the timeframe for improvement in bone density and fracture resilience takes longer. But I would point out to you that in the Orbit study, we are including patients 18-25.
There are adults who are post-pubertal, growth plate fused in the trial, who have high fracture rates. So we will have data in the trial itself for adults, which will help support adult usage. I'm confident adults will need to get treated. I think from a standpoint of the speed of their effect, the peds will be easier, and the trial, and Orbit trials, can be driven more off the peds result. But the adults will be stratified and included in there, and we'll have be able to speak to adult fracture reduction as well. Where do I go? Maybe Gena, I thought.
There's a microphone in the back.
Oh, there's one back there. Okay, you're getting them. All right, I'll let you pick.
Joel Beatty from Baird. What are the implications of today's data for the powering of the Phase III study for Setrusumab? And also, are you targeting a certain amount of patients in the different age groups?
Yes. So do you want to talk about the powering?
Yeah, no, exactly, and I think that's, that's the important part with having access to the pediatric data coming out of phase II. So again, the data we had available to power the phase III part of that study was based on adults. So now with pediatric data, understanding the higher fracture rate there, we really do think we're probably overpowered. We added two interim analyses, so we will have the opportunity to evaluate for that. So it, it's an event-driven study, so we're really looking at the separation of those two groups, those patients randomized to Setrusumab versus on placebo with fracture rate. So, we really do see a path for potential for an early win here.
Okay, Gena Wang from Barclays. So maybe Eric, follow up these questions. So for these two interim analysis you're adding, you said that it's event-driven. Can you share what are the event numbers that for the two interim analysis? And also regarding the age, do you have a set numbers of a patient that's five-12 and 18-26, oh, sorry, 12-18 and 18-26? So that's the first set of questions. Also, I have a second set of questions, very quick, on the, GTX-102. So first, you know, wanted to say like this is indeed, you know, the videos are very impressive. I do have a one question for Dr. Berry-Kravis. So, from, you know, those videos, it's very powerful.
How, from the clinical study perspective, how can we contextualize those change into quantifiable scores? And, you know, we did see many different scores, right? The Bayleys, and today we saw the first time ASA. And then what about the CGI? And if you wanted to, you know, how much differences that could deem to be clinically meaningful?
Good.
Well. Yeah, let's start with the OI. I will deal with the GTX-102.
Yeah, so for the phase III, we're not requiring a set number of patients in each of those groups. We are focused on younger patients. We're showing an emphasis there, but we're not having a set number of patients for each age group, but we are seeing a good number of young patients enrolling in this study, which is important. As Emil pointed out, we do want to enroll some adults. We do want a broad label here. We do think this is an important treatment for children and adults.
Interim timing.
Yeah, the interim timing. So, we're gonna submit the new statistical analysis plan with the FDA, so we don't have full agreement there. We will be looking at, like I said, those two interim analyses there, but I think we'll disclose more detail.
Yeah, I think one of the things to note, the way the trial was designed is that the unblinding plan would be when there was 100% of the fractures required to inform the positive result based on the original power design. So it's the number of fractures, amount of time, and it could anywhere be from one to two years of time exposure. What we'll do in the interims is have looks that are earlier than having 100%, right, less than 100% of the data. So that will allow them to occur significantly earlier during the, as the fractures are accumulating, but the precise date will not be known. It will be based on fractures.
We won't discuss those interims if we're doing them either. They will be done, but the point would be If the power of the study is dramatically higher, and we hit persuasive statistical significance early, we'd wanna end early, both for the ethical nature of treating kids with this disease, as well as because we'd wanna move it toward a filing as promptly as possible. So that's on the interim timing. We would obviously want to stratify for age to make sure we're not having all old in one and all young in another. But let me talk about GTX-102, too. Now, videos, contextualizing. Videos are really supplementary information to look at the quantitatives. Videos themselves are very difficult as endpoints, right? People have looked at trying to develop them, but it is a challenge. What we are looking at is a quantitative endpoint.
We're using the videos to give you context to the quantitative. If we sow, show Bayley Gross Motor improving or the Angelman Severity Assessment of Gross Motor improving, we're saying: Here's the meaning of it in terms of what that means for videos. So, you know, I think it just adds color to it, but I wouldn't say to you that it's going to, It gives us a sense that what we're seeing is clinically important. That is, if we can acquire and demonstrate this level of change in a phase III trial, that this is a treatment that parents are gonna want for their kids, right? That this is a treatment that's important to them, that they can walk without falling, and these are things they can accomplish.
If you look at the. The reason we showed you that emerging developmental skills thing is we try to put it in the parents'. That's the parent's perspective. What can my kid do they never did before? Just to show you that a lot of the kids has five to seven things , even at this lower dose enrollment period of that trial, they had that many first-ever accomplishments. I think that's really the point of it. It's less about the clinical trial design than it is about deciding how important is this treatment, and that's why we brought it to you today, more about the clinical meaningfulness of it. So the Bayley is, has the most historical data. It has. It's quantitative. The Angelman Severity Assessments, I think, are much more Angelman-specific, and so for certain ones, are better. We have other domains, like the.
There's another aberrant behavior scale, which we could potentially use. And we are looking at more endpoints than what I've shown you in the expansion. And our goal is to get a read from FDA what they think will be important and be able to go to them when we have actual expansion data and really nail down what that means. But, the CGI is a possible way of going, but the CGI, we've said many times, is a relative scale. It's not an absolute scale. There is no clinical meaningfulness built into it. It is just a relative scale, a response. For that reason, it has, in my view, it generally hadn't been accepted. They did accept it recently. It was accepted in the Rett program, but not by itself. They had a behavior scale in there, too. Remember, there was two things.
So that means it wasn't standing alone. I would just say to you, I think CGI scores have a utility, but being able to move the Bayley, to me, is show real treatment effect because the Bayley's hard to move. All right, just go on. Where was the next mic? Oh, we have Yigal has it. There's also one person up here.
Thanks a million. Yigal Nochomovitz from Citi. I had two on OI and two on AS. On OI, could you give us a breakdown of the four patients that did have fractures? Can you say which cohorts they were in, in the age groups, five-12, 12-18, 18-26? And then second, with regard to the phase III endpoint, you know, you showed essentially almost as good data with lumping in all the fractures, including the fingers, extremities, face, and skull. So just, can you just explain in a little more detail why it seems like the FDA is more insisting on just the fragility fractures and not including everything, but your data suggests it's as good? And then on AS, regarding the natural history, could you just comment on how the 64 patients were selected?
Was that done with some sort of propensity match score, or was it hand-curated? And then finally, for Dr. Berry-Kravis, you mentioned that the kids don't even know about a placebo effect, so I'm just wondering to what extent they even understand that they're on a therapy for their, for their, for their disease. So if I need to repeat those, I will, but that, those are the three.
All right, I got them. So you want to break out the four patients. The truth is, these are just four patients out of, It's a really small number. The truth is, the four patients that had fractures, half the fractures occurred before three months. Only one fracture occurred after seven months. So part of the thing you have to understand, what we're seeing there is they're starved in the beginning of their treatment course, and I think that's really important. I don't know if you have the breakout. I don't have the breakout in my mind. Do you have the breakout?
No. I mean, we're really looking at them. We're not seeing differences. I mean, you know, we know, for example, the young man in the car accident, he was in the 40 ml per kg dose. The 14-year-old female and the other patient we looked in the wheelchair, they, they were in the 20 ml per kg. But the exact breakdown for those four patients who did experience fractures, I don't have off the top of my head.
We did look at the four patients from a BMD standpoint, and they were near the mean or median of where everyone was, so their BMD response was actually very similar. I think a lot of it has to do with, they were trauma or accident-related, and it was, most of them were early in the course, half of them were early in the course. So I would say to you, it's surprising how few we had overall. That's the thing that's kinda surprising, and that the effect is that fast to be shut down. And I think that's because the new bone being made is made where the bone is weakest, and that's why the strengthening actually can be quite, quite rapid, because of the way bone is produced.
Yeah, and I think fingers, toes, face, and skull is a n interesting conversation that really was at the request of the FDA. I think, you know, some people are trying to make the argument that those types of fractures may not be as clinically significant. I think, to anyone who fractures a finger, face, or a skull would argue otherwise. But I think, you know, with the results we're seeing, you know, it's something, you know, we can align with the FDA on, and we'll certainly look at fractures from both perspectives.
We're gonna do all fractures, too. The truth is, it didn't matter. They just feel like those fractures are more accident-related, not due to weakness of bone kind of thing. But honestly, you could see it. It worked both ways. It didn't matter. So, natural history, the 64 were just based on age and deletion type. That was the selection, that they had, the age and selection type. There was no other. And then, the issue of do they know they're being treated?
Yeah.
Well, they're Angelman kids. They're pretty developmentally delayed. I think to try to determine if that somehow would affect what they do, I'd say is pointless. They can't know what that means to them, right? They're still learning their basics. They're, Angelman kids are like two-year-olds, right? Pretty much. So they're not gonna understand it. I'm sure they're happier when they're calmer and they're, and they're having fun, but I don't think they have any idea what's happening. Let's go on to the next question.
Here.
Who has the mic?
I have it here. I have it here. It's Brendan Smith from TD Cowen. I wanted to ask a little bit about some of the potential seizure data that you have. I wanted to see first if you're actually having the patients and their families maintain a seizure diary in the phase II, and if there's anything you can comment on from there, and potentially how you're thinking about that heading into the end of phase II meeting with FDA. And then also, you know, also on Angelman, kind of looking at the different domains in which you're seeing improvement, obviously you see good in cognition and communication, and a little bit different in some of the other endpoints.
You know, fair enough that these are heterogeneous patients, but if that maybe suggests that the drug is getting a little bit more consistently into the cortex versus maybe some of the deeper brain structures and how we should kinda think about that.
Yeah, so on seizures in Angelman, most of the kids are in good control, and we did not have an issue. Now, there's one of the kids, patient five, clearly had seizures, a problem when he came off, but we haven't noted, we haven't been charting a real effect on seizures that we've been able to see, clearly. We will obviously be monitoring seizures, but I, I would say, Kemi, you have something to offer?
So the trial is designed in a way that patients have to be stable on their antiepileptic drugs and have a stable seizure count. So we don't really expect to see any dramatic change, and we're not measuring seizures as an endpoint for efficacy for that reason, based on the way the current trial is designed. Now, we are, we do have a seizure diary that collects seizures. We also collect information on sleep and the seizure counts that we're collecting are primarily for safety.
Thanks, Kemi. Those are important.
Now the question was on the domains and cortex. I don't think that, w e did the work. The product has been valued, at least in the non-human primate size brain. It showed pretty good penetration. Certainly deep nuclei, maybe not as much, but I would say you'd be hard-pressed to try to correlate clinical endpoints with exactly. One of the things that is important to us is GTX-102 did get to all the brain regions, and we actually did not see a distinction, and I don't think the clinical data tell you a distinction. For example, the motor walking, it's very much a deep brain controlled walking, right? That is, right, walking is part of, is a deep brain-coordinated function. So, I actually think that, I don't think you could draw a connection there.
Who's got the mic?
Hi. Hello?
Hi.
Hi, this is Michael Riad on from Morgan Stanley. For GTX-102 and Angelman, given the benefits on several domains, can the MDRI be applied to the natural history data? And if so, how could that look across the age groups? Thank you.
We certainly could do that. It'd be easy. If you looked at what we saw, none of them got close to the threshold, none of them. So they'd all be blank if we did it, and then we could show a beautiful statistical comparison, and I guess we could do that if we wanted to enhance the analysis. But because you could see the green line in all those graphs, you could see none of the natural history rates were crossing threshold of clinical meaningfulness, so that would have been fine. It would have been one other way to do it, certainly. Someone here has been, had their hand up, and then where is the other one? Okay, who's got it now? You wanna go?
Yeah. Hi, this is Priyanka Grover on for Anupam Rama of JP Morgan. You had previously mentioned when answering the first question, that there is a 20% fracture reduction rate with bisphosphonates, though the literature is a little all over the place on this. How confident are you on this assumption as it relates to putting Setrusumab fracture rate data into context?
Well, the thing with fracture rate reduction, you have to look at the powered studies that actually did a randomized powered design to look at treatment effect size. 'Cause if you look at a small study of 20 patients, and they do something, come up with numbers, then you're dealing with skewed data, right? So to really get a good treatment effect size, that's when you should use the two out of the five studies that were randomized, controlled, with enough power to really do a proper ascertainment. Those studies give you about 20%. I think the truth is that all the patients in this trial, all those fractures you're talking about, those are all people on bisphosphonates. So whatever it is, they're all fracturing still. So I'm really not concerned about bisphosphonates as a control group.
It is not that good at controlling fractures. It's just not. It isn't. And the truth is, to strengthen their bones, you need bone anabolic effect. It's not a question of preventing resorption. It's a question of laying down bone where the bone is weak, and these kids just don't. So I'm actually, really, we don't have much concern now. The trial itself is perceived controlled, right? So the control group could have been on bisphosphonates and would have bisphosphonates in their bones, but that could be true in both groups, but that effect would be waning as time goes on.
We do have that second Phase III study to support ORBIT, and that is a head-to-head Setrusumab to bisphosphonate, so we will be generating our own data there.
We have no fear about that one, the drug Setrusumab's effects will be so much greater on BMD, and done the right way, it'll be, we think, much superior. I think, who's got a mic?
Right here. Dae Gon from Stifel. A couple questions, starting with OI. If we look at the trial conduct itself, I think you mentioned or one of the docs mentioned that parents have gotten so used to fractures. How frequent are these patients being called in to measure their radiographic fractures, just so we you know, you don't miss any of those in real world? In terms of AS, if we look at the patients 14, 15 in the cohort four through seven, the extension, I believe, I think they had the least amount of improvements, and I think one of the remarks was, at age four, your curve kind of flattens out. Can you comment on the 14, 15 patients' age and what their current status is?
If we can kind of get some clarity on that, that'd be great. Thanks.
You know, so t he first question was on the fractures.
Yeah.
Yeah, so important question, because we do know, and we've heard very consistently, that parents are underreporting fractures in their children out in the real world. So we're really trying to ask them to err on the side of caution. "If you're having the type of trauma that would have historically generated a fracture, come in for X-rays." So yes, we do have set intervals where they're coming in for evaluation and clinical exam, but more importantly, we're really communicating, and this is where training comes into play here, is that when you do have that, that type of trauma, you are coming in for X-ray evaluation. And we're really looking not at just suspected fractures, but for our primary endpoint, radiographically.
Are being seen monthly in the way that the 'cause of the treatment, so it does assure that we're capturing things. There will be a skeletal survey at one year, which allows to look for subclinical fractures and look for healing fractures as well. So you asked about the 14, 15, patient 14, 15. I don't think I wanna get into the details. Each patient is a little bit different. I don't. The older patients may respond differently than the younger patients, but the truth is, there's a lot of variability in what these patients are, but I can't tell you there's anything you're gonna be able to glean from understanding who they are. I would say we've seen older patients respond, younger patients respond.
I think it's expected the younger patient will respond better in certain ways, but the older patients, some of them have been, for example, better in gross motor, in walking improvement, mainly 'cause their walking is so much poorer at baseline that you can see the improvement. So I think it's. I don't think I would gain much insight from that. I think, Liisa, are you next?
Yeah.
We have one in the back. I think she's had her hand up a while.
Oh, I've tried to track. Okay.
Salveen Richter, Goldman Sachs. With regard to the Angelman's program, you plan to discuss endpoints with the FDA early next year. What would you see as a positive outcome here, or what are you expecting in line with the receptivity you've had to date on the multi-symptom domain?
Yeah, Salveen, I think they, at our last meeting, they seemed open to a lot of ideas, and that's partly why they wanted us to go talk to COA, the Clinical Outcome Assessment group, and to talk with them. I think they were open to understanding it's a complex disease and a first-time-ever treatment. Our discussion, initial discussion, is to pitch them ideas on how to go about this. Our, my personal bias is toward the multi-domain responder index, only because it allows us to capture benefit in different patients who have different situations. You heard 30% of the patients have severe sleep problems, but those problems are profound for that family. I'd like to be able to capture that in the primary endpoint, but it may not be everyone. The walking problems, language are pretty common for everyone.
So I think that discussion is hard to know. They haven't really guided us exactly on one thing or another. They've certainly not told us CGI, for example. They did not say that at all, right? That's not something we've talked about. I think people understand the Bayley and they understand the others, and they're interested in understanding the supporting data on the endpoint and its relevance to Angelman syndrome. So we're doing that work to try to show how those quantitative endpoints relate and how they are validated for use in Angelman, but right now, I don't think they've given us a tip, tipped their hand one way or the other.
I think it's really up to us, by the way, to do the right science and to present our case, and in the past, we've been able to get the right things done with the agency, but we have to present our case well. Next question. Oh, right here, Liisa.
Oh, hi.
Yeah.
Liisa Bayko from Evercore ISI. I was just. My first question is on Setrusumab. Curious about the four patients that had some fractures. Was there anything different about those patients, that they had the same level of bone mineral density, you know, after treatment or anything that you could identify why they might have responded differently? And then also, could you talk about the data in the context of means? I know you used medians there, and I'm just curious, if there's any differences.
Yeah, so means, medians. We've mentioned the four patients I did just a while ago. So those, the bone mineral density of those four were at the mean or mean. They, they're like all the rest. Most of those kids had traumatic events. Something happened that correlated, and half the fractures were before they had been on drug very long. So if you cut away half the fractures with that, and then you have some traumatic events, I think they respond to the same. So they're not nothing wrong with them. They just, they just got unlucky. They were slip on black ice or whatever happened. There's different things that they did that got fell on their arm and all that. So I actually think there's nothing different about them. Liisa, do you agree with that?
Yeah, no, and I think, you know, looking at bone mineral density, we're not seeing a difference. We're not seeing them as slower to respond or weaker responders. The difference is time on treatment and then degree, really the degree of trauma there.
Good. I think we'll go with one more. I think we're time. We've burned through our time. Thank you for all the great questions. Is there one more? Where is it?
Yeah. Hi, Kristen Kluska at Cantor Fitzgerald. I wanted to ask about the trends and what you're seeing after 12 months, especially given that this is a limitation for Romo. And then how are you thinking about pricing early on here with the potential for off-label usage? Thanks again.
Yeah. So you actually saw the one kid that Eric presented that had been on 17 months. I think the data. Remember, we have no fractures after seven months in anybody, right? So there is a potential that this could dramatically reduce fractures in these kids in the long run, which would be amazing. The truth is that this, for safety reasons, Romo is limited to 12 months in osteoporosis, and that is all they're doing. They have a hard stop at 12 months, and they discontinue. We're, we're not. We're, we're actually planning, and we have not had any pushback from FDA of going chronic.
Now, we think once the kids reach a certain bone mineral density, and once they have stopped having fractures, there may be a point at which we move them to a maintenance dose, where it might be every two or three months, let's say. Based on the ASTRO study, where they stopped them at 12 months and then looked at withdrawal, BMD followed them. They were okay until about two to three months, and then they started losing ground. Their bones started going back the other way. So it looked like if you stimulate them every two to three months, you might keep them from a steady state. So that's the way we're looking at it. I think the competitive issue with Romo, Romo works. Romo is another anti-sclerostin, it clearly works. Amgen is not interested in it.
They have given us a non-exclusive license to the epitope patent. Tells you they're not interested because Amgen would never give rights to a patent they were not interested in. And that's a royalty-free. It's like a license fee type deal, not a no royalty involved. And they are doing what they're doing because it's precisely required in their PIP to do this, but I don't think they're putting it on a label. So the question is: could people still use it off-label? And I think that is a potential, but they won't have the services we have in support of patients, co-pay support, and the rest of it that we do. They won't have home infusion, other approaches. So there are things we have to think about.
But we've said as a company that we will be conscious about repricing, and we've always been a company focused on responsible pricing, just as we did for Crysvita. And we'd have to look at how, what the off-label risks are, and I believe that a reasonable price differential will not cause a problem. And with the combined improvement in services, we think it won't be, it won't be a resistance, particularly since our drug will have been proven safe and effective in the indication, and that it will have long-term treatment effect data. It's also a fully human antibody, not humanized. Fully human for chronic treatment is always better, right? The immunological risk, we have no anti-drug antibody issues. So you look at a number of those features and the care we'll provide to our patients, I'm less concerned about it.
But I think you also have to be conscious of an extreme price differential, could create more of a problem, and but we'll be a responsible price company. We think about how many patients are in unmet need, and if the effect we're seeing so far translates in phase III, I can see this being, you know, first-line care for basically, most OI patients. So we see this as a tremendous win, and we'll manage the competition when we get there. Good. Thank you. I'm sorry. I'm sure there are more questions, but we've, we've blown our time. It's time for a break. So a brief break, and then we'll be back. Thank you. 10-minute break.
Time for musical chair.
What's that?
You can take your bag off the stage.
Not sure what difference it makes, but I do what I'm told.
Yeah.
Good to see a lift with the data. Yeah, about time. Emil, you have fresh tea.
I have fresh tea.
So what do you want me to do with time?
Just go to your normal cadence.
All right.
Normal cadence. You don't have to accelerate.
Nope, normal.
Okay.
You ready to get going?
Okay.
I'll go ahead and get started.
Yeah.
All right, great. Thank you, everyone. We're now gonna shift over to looking at our gene therapy programs. I'll do a clinical overview, and then I'll hand over to Dennis to do a walkthrough with our manufacturing platform. So this is our pipeline within a pipeline. To my knowledge, this is the largest and most advanced gene therapy portfolio out there, particularly in rare disease. These are our six active programs. four out of six of these programs are in pivotal trials. This includes DTX401 for the treatment of glycogen storage disorder, our lead liver-directed gene therapy program in a traditional phase III. UX111 that we brought into the portfolio about a year and a half ago. This is a peripherally administered gene therapy affecting a neurologic indication, MPS IIIA.
DTX301 for the treatment of ornithine transcarbamylase or urea cycle defect, and then importantly, our newest liver-directed gene therapy, UX701, for the potential treatment of Wilson disease. We are including this and counting this in a pivotal trial because with the learnings we have gained with these earlier programs, we were able to bring forward and come to agreement with the FDA and other agencies on a seamless phase II/III design. That's important because that allows us to move forward without stopping for end-of-phase II discussions with the FDA or scientific advice in Europe. Really does accelerate developmental timelines and allows us to get these important treatments to patients as quickly as possible. With those important learnings, we were also able to diversify outside of the liver and beyond, peripherally administered gene therapy.
We're bringing forward UX055, a gene therapy administered directly into the central nervous system. This is for CDD or CDKL5 deficiency. And then again, really importantly, now looking at large muscle diseases with our newest preclinical program for UX810, gene therapy for the potential treatment of Duchenne muscular dystrophy. Quickly looking at these diseases individually, again, gene therapy for GSD Ia is our most advanced liver-directed gene therapy program here. This is a disorder of energy metabolism. These patients are not able to break down glycogen to produce glucose during times of fasting. So this means that these patients get into trouble very quickly. Their glucose levels can plummet, they can start to have seizures, and these really can become life-threatening events, particularly in the pediatric age range.
There is really no treatments available for patients today, and what they have found useful is the use of uncooked cornstarch, because cornstarch in its uncooked form is very slowly metabolized by the GI tract, so it is providing some source of glucose during times of fasting. These patients are dependent on cornstarch for life, meaning they have to take it every day, several times a day for life, but also dependent on life because a single missed dose, again, particularly in younger patients, particularly overnight while they're sleeping, a single missed dose can result in a fatal event for these children. What you're seeing here is a picture of what one of our adult patients packed to go on a long weekend trip. He doesn't trust that he can get cornstarch when he gets to where he's going, so he brings it with him.
After treatment with DTX401, he now just brings a single box, kind of as a safety blanket here, and really, you know, really shows the impact this, this drug have. They're able to really lead a normal, active life, travel, do things they weren't able to do without having to worry about how are they gonna maintain their glucose levels. Patient in the phase one study continue to do very well. All patients are in their fifth year of treatment. All patients continue to respond, and this reduction in cornstarch while maintaining glucose levels will be our primary endpoint for our ongoing phase III study, which fully enrolled at the beginning of this year and with a data readout, first half of next year.
Shifting now to our first neurologic indication, this is a peripherally administered gene therapy, but affecting a predominantly CNS disease, Sanfilippo or MPS IIIA. As I mentioned, we brought this program into our portfolio about a year and a half ago. The ongoing transfer study was originally designed to be a phase I/II study. The data out of that study is so compelling and really drove the reason why we wanted to bring this study in-house, allowed us to have negotiations with the FDA to consider this the pivotal data set, and we will not need to do a new study for registration. Original agreement was to follow these patients to their fifth birthday, really looking at a clinical endpoint. By patients' fifth year of age, by natural history, they really all have deteriorated to a meaningful degree.
We do think this is a very good opportunity to look at a biomarker approach here. Heparan sulfate is what accumulates in these lysosomes. It is what drives pathology and clinical signs and symptoms, and we are having ongoing conversations with FDA about a biomarker approach here, and, you know, we'll continue to have these discussions as we approach the end of the year. Our next liver-directed gene therapy program for OTC or ornithine transcarbamylase deficiency, this is a urea cycle defect. Urea is made to break down ammonia. Ammonia comes from the ingestion of protein and the breakdown from muscle. We do not tolerate ammonias above the upper limit of normal. It's a very potent neurotoxin.
So with this enzymatic deficiency, you can very quickly get into trouble with a metabolic stress, taking in too much protein, having a viral infection, and after treatment with DTX301, we're seeing seven out of 11 patients being responders, being either having the ability to come off their current standard of care, alternate pathway medications, and protein-restricted diet fully or to at least a 50%. These patients also in at least their fifth year of follow-up. So these this program is also in a traditional phase III program, enrolling very well, and looking to fully enroll that patient in that clinical study in the first half of next year. A little more time here with Wilson. We're really excited about this new, also liver-directed gene therapy program.
We really weren't able to look at these types of diseases with this type of incidence and prevalence without the advancement of our manufacturing platform and really bringing forward the Pinnacle PCL platform. Building our manufacturing facility outside of the Boston-Cambridge area has really enabled us to look at these larger indications. Wilson is a disorder of copper trafficking. Copper, free copper is also very toxic to the body. This genetic defect leads to the inability to transport copper out of a liver cell, out of a hepatocyte, either into bile for excretion out of the body or for loading of copper onto ceruloplasmin, which is how it needs to normally traffic to other cells and tissue, where copper acts as an important cofactor for enzymes.
So we're really looking at this, this disease as a copper toxicity in excess of free copper, but also a functional copper deficiency because you're not able to get co-copper where it needs to be, a gain, leveraging all the experience we've gained over the years, looking at a seamless phase I/II study. Because we do need to establish initial safety and select a dose for generating our pivotal data set, we're looking at Stage I. We are looking at three cohorts, starting with 5E12, moving to 1E13, and then 2E13, and then moving to Stage II, which will be generating the pivotal data set. We recently had a data readout to support moving to Cohort II, Dose II or 1E13. And what you see here is, these five patients lifted out.
We listed out, we do enroll them sequentially, so you see the time and study here. With Patients two and three, longer on study, really promising results here. We are seeing the copper biomarkers move in the correct direction. We are seeing data from a functional assay, which actually measures the direct loading of copper onto ceruloplasmin. With chelators, you're simply binding copper out of circulation. With zinc, you're preventing absorption from the GI tract. So if we're able to measure and see an improvement in the loading of copper onto ceruloplasmin, that really is directly showing the effect of this transgene. So seeing these patients, Patients two and three, completely off of standard of care, seeing the biomarkers moving in the right direction, and importantly, having them telling us how much better they feel, we see this as a very promising signal.
Patient four and five, a little bit earlier on in follow-up, they are actively titrating. Patient four is currently recovering from COVID, so a little bit of a pause there. But with 33% and 50% reduction at 20 and 16 weeks respectively, again, really promising result for these first five patients. We have fully enrolled Cohort II at 1E13. We have all patients identified and deemed eligible for Cohort III. So looking to quickly complete Stage I, which will allow us to seamlessly move to Stage II and generate that pivotal data set for registration. All right, now I'd like to hand it over to Dennis Huang, our Chief Technical Operations Officer.
Thanks, Eric. So we'll pivot here a little bit and move from the clinical view of things and begin talking a little bit about the technology, because as you know, gene therapy programs are inherently highly technical, and also being a more cutting-edge type technology, have shown in various programs moving forward here that the technology or the CMC side of things can actually be an impediment to drug development. So as Eric mentioned earlier, many of our older programs use the HEK 293 suspension process or system, and we currently run those for our GSD programs and our OTC programs, indicated there, DTX401 and DTX301. What I'll also be spending most of my time talking to you about really is our Pinnacle platform, Pinnacle PCL platform, which stands for Producer Cell Line.
That really is the way forward for us, as a, as a business, as a company, and really, enables a lot of different capabilities that we believe, will really lift up the whole area of AAV gene therapy. With regard to Wilson's, this is the first program where we've really turned it on, if you will, and built a, and enabled a, a really tight integration. As you, as Eric mentioned earlier, the Wilson's program is, is really the prototype with which we are going to be moving forward, both from a clinical design perspective, but then also from a technical base. So as an example, one of the things that we're really keen on with this Pinnacle platform is, certainly reduced cost of manufacturing.
That typically has been a very significant cost element within the development cycle, but also maintaining that all the way through not only the clinical development, but through the commercialization, and I'll talk a little bit about that in certainly much more detail. But the other aspects of it is, for the CMC program, in, to match that integrated approach that we're taking, we have not had to do any sort of scale changes as part of this Wilson's program. We've started out at that 2K, and so you see a picture of that over there at the 2000-liter scale. That has enabled us to really minimize the supply chain challenges that you typically would see, or doing scaling up and making CMC changes through the life of the program.
So fundamentally, what we'll be sharing here is this process and this technology really enables us to expand our worldwide patient access ability to dose at much higher levels that probably wouldn't be possible, and then really just the much, much larger market opportunities. So we've not only invested in the technology, but we've also invested in a lot of internal capabilities. And so when we acquired Dimension Therapeutics in 2017, we already had a very established research and development area. And so we've pumped in a lot of effort and energy into those groups and have expanded their capabilities in the Boston area. Subsequently, we then added GMP manufacturing capabilities in QC laboratories, which also tends to be a bit of a bottleneck for many of these gene therapy programs in 2019.
And then, as Eric mentioned, you see the nice, shiny picture of our new facility, our GMP manufacturing facility, which just came online earlier this year. So this facility has not only drug substance, but drug product capabilities. It is designed to both produce our HEK 293 platforms, but also, just as importantly, our Pinnacle platforms. And again, this is based on the 2,000-liter scale, though, part of the reason why we selected that scale is really tied to the fact that for rare diseases, we probably don't need that big. But from a technology standpoint, it's much, it's capable of going much higher, and I'll show you that shortly. So if we're comparing these two different processes, this is sort of one way of showing the differences here.
As I mentioned before, the commercial scale is really critical because going back to the changes that you typically do during a clinical development, we're starting out at the commercial scale, and so we're minimizing the need for changes, those CMC-type changes that can slow down programs very significantly during the course of that, and that's one way of us minimizing and making a very time-efficient and cost-efficient development life cycle. The second piece here really refers to how stable this cell line is, and I'll go through in a little more detail about why we or how this PCL is developed and what makes that important in terms of supporting our programs.
Quality attributes are really key here as well, and just, I'm sharing just one example here where in the Pinnacle PCL platform, because of the way it's engineered and, sort of leveraging, this Ad5 approach that we're talking about here, really creates much higher, quality, full capsids coming out of the bioreactor. Okay? And so typically in a, maybe HEK 293 process, we'd see something in the 20%-25% coming straight out of the bioreactor. For the Pinnacle PCL process, we start out at a much higher level. And so you can imagine that starting at a higher level, cleaning it up, and doing all the things you do just creates much better economics from the get-go and reduces, fundamentally, and this shows in the last row here, the cost of manufacturing.
This can be a very expensive therapy to produce, to manufacture, and certainly we expect to get much lower cost of manufacturing with our Pinnacle PCL platform, very comfortably getting below the $100K per patient dosing range. And in fact, for the Wilson's, we were able to achieve that even during the clinical phases I mentioned. So let's delve a little bit. I've just got one slide that looks like a cartoon, but this particular slide just articulates a little bit the elements that come together in our Pinnacle producer cell line platform, that's really geared towards high titer and creating, therefore, commercial viability. All starts on the far left there with the producer cell line, and that's by definition what this process is.
This work was first started, or first described in the mid-1990s, so this has been around for a while, actually by our gene therapy chief scientific officer, Reed Clark. And so he did that work, initially as an academician in Ohio State, and we licensed it from there and combined with the producer cell line with this Ad5 helper virus. And what that does for us is it creates a, a very simple formula, if you will. Now, compare that or contrast that with the HEK 293, where you add DNA plasmids to it instead of the, helper virus, where.
And all those plasmids create a lot of additional costs because those are not particularly cheap, but then also from a thermodynamic standpoint, probably creating some challenges with regard to creating full capsids, which is what is represented here in the far green. On the far right-hand side in the green is, is the product that we're after. So, a big quality attribute that I mentioned before are the percent full, and so the bigger the number, the higher the number, the more it is a better thing for patients and so forth. This slide here really indicates the improvements that we've made over the years since acquiring Dimension in 2017.
One of the things I also want to mention on this slide is that, we first introduced clinically, this PCL, the early forms of it, in 2015, so this is a clinically validated, sort of methodology or approach. And obviously, you're hearing about the Wilson's program, which is also sort of illustrated here with the yellow 2019 technology. But the main point here with this slide is, since the time that we've taken over, this technology, we've really invested a lot and made some significant improvements in that time. One of the examples that I'll be sharing with you is related to the Duchenne program or the 8/10 program. As part of the 8/10 program, we really had a number of challenges because of both the prevalence, the population, higher dosing.
This particular challenge was identified pretty early on. One of the things we appreciate about our PCL, our Pinnacle PCL platform, is the fact that it abides by or really takes proven, what I would say, biotechnology. So if I go back to my earlier career in recombinant proteins and so forth, a lot of those technologies, batch fed, you know, fermenters and all those kinds of things, many of those technologies or improvement strategies are sometimes called in the field, you know, intensification approaches, apply directly to what we're doing here with the Pinnacle PCL platform. We feel very confident that using those proven approaches, we'll be able to enhance very quickly, and we have shown very quickly, improvements in yield and titer and quality, all the things that you're looking for in a low-cost therapeutic.
So we've developed what we call our APEX process, which is an AAV profusion-enhanced expression system, and this has now been applied to our 810 process. So a couple of slides or a couple of panels here on the left-hand side show you some of the changes that we've made and the improvements we made using this profusion system. The benefits of this really are, as I said before, the engineering control of this, the scaling of this. So I mentioned, it's regularly, easily achieved, much higher in traditional biotech programs, you know, instead of 2K going up to 10, 12, 25K. So in principle, this, because this applies, is very relevant to our system here, could be scaled very easily for larger indications and therefore, economies of scale.
And again, reduced COGS. So while the Wilson's program is definitely, the technology associated with was very good, we've subsequently added additional improvements to this, and that was the example that I was just sharing with you around, the Duchenne program, and then potentially even larger indications or larger dosed indications. So hopefully, been able to share a little bit of some of our excitement around how we believe this Pinnacle PCL platform can really transform this area of AAV gene therapy to, touch on not only liver disease, neurological and, musculoskeletal. This is something that we've invested a fair bit and are now just to the point where, we're able to sort of visualize and see that path forward based off of our internal capabilities.
My final slide here really just talks about the fact that if you compare this to other technologies in the past, monoclonals, recombinant protein technologies of the 1990s and 2000s, standardization on those things have really helped us move that technology forward, and more importantly, better helping and treating our patients more quickly. More recently, the mRNA with COVID vaccines is now, I would argue, become the standard for those types of treatments. The Pinnacle PCL platform that we've developed really has a lot of the right characteristics. It's clinically validated. We've demonstrated it can be cost-effective, certainly efficient from a time-development timeline, without making changes during that life cycle, high quality and scalable product. So those are conclusions around my remarks.
I'll turn it over to Emil to talk a little bit more about an application of this Pinnacle platform.
Thanks, Dennis. We thought it important to talk about the Pinnacle platform, the gene therapy franchise, cause I think AAV has been in a challenging place, but I think there's ways to make it more accessible, more cost-efficient, and I think Pinnacle is one of the ways to do that. The question, though, people think at $3 million price point, who you're gonna treat, and how does that work? And I think that's because it's early. But we think with the platform, we can actually do something much greater. In fact, we think it's also possible to reach larger market disorders through the manufacturing improvements of the Pinnacle PCL platform. What I want to do is talk to you about another indication, a very large indication, which we've now have discovered some insights on that we could potentially use with AAV.
I will talk to you now, the last topic will be a novel gene therapy therapeutic approach to targeting beta amyloid accumulation that builds off some of our historical information. And this is a project that's gone on a very low key at the company, very small spend, but has come up with something very exciting, and the pinnacle platform enables us now to consider potentially even as large indication as Alzheimer's. So to give you a summary, we, you may know in the past we worked on galactosidosis and enzyme replacement therapy that we stopped. But while we were working on it and working with Sandra D'Azzo at St. Jude on the enzyme PPCA, we discovered something about PPCA, that it actually cleaves Aβ42 very efficiently, in fact, can actually disaggregate Aβ42 , and we were very encouraged by this activity.
But from my own experiences as a scientist and as a lysosomal biologist, I always had the feeling that Alzheimer's and all the beta pleated sheet proteins are due to accumulation of beta pleated sheet, that the lysosomes are not adequately cleaving it. And so we know Alzheimer's is complex. We know now that beta amyloid accumulation is clearly a problem, that it's resurgent, and the monoclonal antibodies now are clearly have an effect. But their effect is still modest, decreasing decline, but not yet solved. But Alzheimer's and lysosomal disease are actually in more peril than you realize, and I'll talk through those today and show you why actually providing supple amounts of PPCA can actually clear amyloid, and as an alternative to using monoclonal antibodies, and we'll show you data in the 5XFAD mouse today. Now, this is obviously something that Ultragenyx would do.
We're a rare disease company. We're not going into Alzheimer's right now, but the idea would be, we could put this into another entity and actually have that be pursued. And we think, frankly, with the success we've seen so far in it, it seems like an essential thing to do. This needs to be tested and moved forward. So let me talk through the data and then our plans going forward. So the amyloid hypothesis has been on again, off again, on again. I think it's clear that amyloid matters and that you can affect and have an impact on Alzheimer's disease, on cleaving or getting rid of Aβ42 oligomers. What's not been so clear to people is: Where does it really go? Where are the problems?
And in fact, if you look at a lot of the lysosomal disorders, they have many of the same features, and there's clearly some relationship between the two. And I think from the work I've seen done, there's actually a very precise pathological alignment between what you see in Alzheimer's pathology in the brain and what you see in lysosomal diseases. My own mentor, Lewis Neufeld, studied MPS IIIB and showed it had a tau tauopathy, was very similar to Alzheimer's, capping and all the other pathologic features of Alzheimer's. Sandra D'Azzo studied Sialidosis and showed massive Aβ plaque accumulation with the deficiency of neuraminidase. And if you look at all the stories of lysosomal disease, you see this pattern.
But more than that, if you look at Alzheimer's studies and researches, more and more just data behind the idea of lysosomal dysfunction in Alzheimer's, and that these features are not true to unrelated. These are actually related because I think there is a relationship between the biology that's going on between the two. And so what direct evidence of lysosomal disease now has of lysosomal involvement in Alzheimer's has been shown in a number of studies, but Dr. Ralph Nixon probably has the best data, and he recently published some work showing activated lysosomal function in Alzheimer's brain. And clearly, there's a shift toward thinking about the involvement of lysosome involved in amyloid production. And so that connection, we think, is actually more important than people realize.
And based on the therapeutic data we're gonna show you, there's a distinct connection, what's going on in lysosome and what you're just seeing with plaque outside the cells. So let me talk a little about the PPCA enzyme. I'm giving you a short course on biochemistry very quickly to it. PPCA, protective protein cathepsin A. It's a cathepsin is a protease. It's a lysosomal protease. It actually forms a complex with neuraminidase in the lysosome, something Sandra D'Azzo discovered. PPCA itself is a carboxypeptidase. It cleaves the C terminus of proteins. It's highly selective for hydrophobic amino acids, which are very much part of Aβ42 at the C terminus. It also recruits. PPCA will recruit neuraminidase to the lysosome, and neuraminidase regulates lysosomal exocytosis and lysosomal biology.
So when you give PPCA, you're actually giving PPCA and NEU1 together in a sense, and that's changing the biology of lysosomal degradation. Now, we did some early work with PPCA, and if you look at the sequence it cleaves, it aligns very well what you see at the C terminus of Aβ42. And the C terminus of Aβ42 is actually very important because the C terminus forms a, like a lipid zipper that assembles Aβ. You need the C terminus. If you get rid of the C terminus, it will not form, it'll actually disassemble. And what we've shown in vitro, if you take Aβ42 in vitro, that we will cleave. And if you look at the bottom left there, you can see LC-mass spec, where we chew in half the Aβ from the C terminus with the enzyme.
We can show that if you put A beta 42 in what's called an aggregation assay, amyloid aggregation assay, under the right conditions, then instead of forming amyloid with small amounts of PPCA, you can prevent the amyloid aggregation from occurring. In fact, you're digesting, if you look at the Western blot below, oligomers are being digested. But if you look carefully above, you can also see the high molecular weight fibrils are actually disappearing, too. What you're actually is disassembling these oligomers and digesting them both. This is very interesting for us. This is in vitro. The question is whether this would happen in vivo and how would it relate to what's going on in an Alzheimer's model. We did some experiments. I won't go through all of them.
We've done a number of them, but I'll show you one of them just to give you a sample. The 5xFAD mouse is an Alzheimer's model that has five different mutations. It's the most aggressive Alzheimer's mouse, has the most rapid amyloid accumulation. And if you look at the data that's been published, no one of the monoclonal antibodies has published data enough for this mouse because it's so severe. But we've taken this model as the most severe model and done some work. The experiment I'm gonna show you, the mice were started on treatment at 14 weeks. They're given a single injection of AAV that expresses PPCA and then taken down 12 weeks later. And we've done this experiment in various forms and repeated it a number of times, but what we can show at baseline, there's already significant amyloid beginning.
In the control animals, you see a massive between 5%-15% of the brain surface by quantitation is amyloid now in just 12 weeks. All right? But if you treat with PPCA, you can see a substantial reduction or elimination of amyloid. The three mice that not the most are actually the ones that had the lowest expression. So if you achieve a level of expression, you essentially reverse it. And we measure this in various parts of the brain in very different ways. I'm just showing you one example. If you look at the immunochemistry, on the upper left is the baseline before treatment, showing already amyloid at the 14-week point, significant amyloid already across the brain, and below is the vehicle-treated animal at 12 weeks, showing massive amyloid accumulation, right?
The two treated animals on the right show the bright green is where PPCA is being expressed, and you can see in the upper section, essentially no amyloid remaining. The PPCA is made in those cells. At certain part of the brain, the enzyme, it gets secreted in a pro form. The enzyme then get retaken up by other cells and essentially arm them with the peptidase that can cleave amyloid, and we see a significant reduction, or in some cases, elimination of amyloid. If you look more closely at the images, and we're zooming in here, on the left is sort of what vehicle looks like, and you can see the frothy plaque, not very much of it in the lysosomes or in the perinuclear area, but most of it extracellular. When we do the treated animals, you start seeing particles of amyloid actually in the lysosome.
If you look carefully, you can see some of them are yellow. The ones that are yellow are having PPCA, and the amyloid pieces are in the same compartment, right? That's how they turned yellow. You can see the high-expressing green cells that are making enzyme cross-correcting cells around them, who are now able to process the amyloid, the particulate amyloid and plaque. This is essentially, you're seeing the plaques essentially being digested. The question here, and this is the crazy part, is the plaques are outside the cell, and the enzyme, we're putting a lysosomal enzyme in the lysosome. How is it that placing a lysosomal enzyme in the lysosome, it's only active in the lysosome, is removing plaque outside the cell? Well, the truth is, the plaque outside the cell is actually coming into the cell and coming back out again.
It has a path through the lysosome, and the plaques are connected to each other. We just don't see that 'cause we don't see the pathologic process. The plaque is the car crash. The brakes are broken inside the cell, and the car is crashed, and you look at the crash, and you're trying to figure out what happened. The problem is that the brakes inside the lysosome for cleaving amyloid and getting rid are gone, and that's why you keep, you keep dumping and have seen car crashes outside the cell. So we can actually put a lysosomal enzyme in the lysosome and affect plaque outside the cell. This should be illuminating on what's really going on and a fundamental shift of thinking, and it fits well with Dr. Nixon's work and Dr. D'Azzo's work, that the lysosome is really important.
The second point I'd say is, where are the toxic oligomers everyone talks about? Where are they actually? Are they floating around? Well, I think they're actually in the lysosome, and the reason they're toxic is 'cause they're assembling into in the acidic environment, they're assembling into fibrils. They're rupturing lysosome, killing cells, and that's why they're toxic. And then once they kill the cells, the plaque's dumped, it ends up outside, gets taken up again, and I've shown you in our pictures, pieces of plaque back inside cells again. What we're doing with PPCA is giving the cells the extra tool, protease, to help digest the plaque when they have it, allow them to eliminate the plaque, and this enzyme is particularly good for Aβ42 because of its specificity for the C terminus, which helps disassemble plaque.
So we're very excited about this result, but obviously, it's something that's hard for us to do. But I wanna say one more thing about enzyme versus antibody. I'm an enzyme guy, right? Now, we have an antibody product, it's Setrusumab, but enzymes are more powerful. And this is just the point to think about here. When you give a monoclonal antibody, I'm always impressed with the fact that you actually have to give more grams of antibody than you have amyloid in your, t hat they're binding. That you have a 180-kilodalton protein to bind two 4-kilodalton peptides. That's kind of a strange ratio, right? You actually have to give more enzyme. So the problem with monoclonals is you have to give a lot of them. Even if they bind oligomers, it's still more protein in the antibody.
And so you're getting inflammation by this antibody because it turns on macrophages. The inflammation causes ARIA, and you have a limit to how much amyloid can you bind up, which is why you have to treat things early. But what if you had an enzyme? Well, the enzyme that cleaves 35 Aβs a second. One enzyme of 55 kilodaltons will cleave thousands of peptides. The stoichiometry is just dramatically better, and dramatically better for what would be needed to achieve treatment in more advanced amount of amyloid. How does that compare? Well, if you compare what we're doing with PPCA and the monoclonal antibodies that have been approved, you can see that we're working in the 5xFAD mouse, the worst, most rapidly progressive amyloid-producing mouse, and we achieve greater than 60% reduction in amyloid in that most difficult model.
If you look at the others, they're only working in the 2x model, which is much slower, takes months to get accumulation, and their best is 30%-50%. That's the difference between an enzyme and an antibody in terms of potency. It opens the door then to perhaps an enzyme delivered with a gene therapy could be a way to arm the cells with enough enzyme to actually give them the ability to process their own amyloid, which they're now unable to do. So our Pinnacle PCL platform puts us in position to do this. We actually can get the costs down to maybe $10,000-$50,000 a patient for a single-dose therapy. And imagine getting one infusion instead of over a five year period, having something like 100 or 200 infusions, right, for a monoclonal antibody, a one-time treatment.
If we can get the cost in that range and optimize CNS delivery to get the activity required, it does open the door to large market CNS indications with this platform. So summary, as I've said, Ultragenyx is not gonna go into the Alzheimer's field. Don't worry. But it's too important a finding not to do, not to have be done. So the right way to do it is to put it into its own entity. We're calling it Amlogenyx. We'll have a majority interest in it. We're seeking outside funding currently, and are entertaining talking to a number of investors. Our hope is to finish a Series A by the end of the year. It'll have our IP in it, our platform, and our ability to help manufacture it.
The program will be cash neutral with Amlogenyx, so it won't alter our commitment to our key value drivers and our burn goal, targets, et cetera. But I couldn't sit by and watch something this exciting and not actually put it into play and to make it potentially available. And I could see this just being a leap ahead in how you might treat Alzheimer's, far better than infusing monoclonal antibodies. So that's that story. That was surprising, right? A little excitement, a little buzz? Ooh. Yeah, should be. So, we'll go right into closing remarks. It's been a long day, I realize, but it's gotta be an exciting day. We've talked about three major programs, and I just threw another huge program at the end. But transformed treatment for UX143, so treatment for osteogenesis imperfecta. The doctors' jaws dropped.
The amount of improvement is just staggering because they didn't think that making more bone with this patient would do that, but it is doing that because the bone is not bad bone. The bone they make is still good bone. They're just not making enough. It may not be perfect bone, but it's good bone, and the patients are strengthening. Potentially transformative if we are able to achieve eliminating fractures as a common occurrence, that is transformative, especially if you imagine doing it from a 1 or 2-year-old. The Angelman story has had a lot of ups and downs, but it's been all up for us. It's just that down's for other people. So I don't know. We hopefully tried to give you a little more of what we've seen and feel, right?
So you know when I say there's time and dose-dependent improvements, that you say, "Oh, it was true. It is- there is time and dose-dependent improvement," and, "Wow, this is powerful." Because we're changing the quantitatives, we're exceeding natural history. We show you quantitative EEG improvements, and we've shown how that's clinically meaningful, meeting clinical meaningful thresholds. And we've shown how it's meaningful for patients in terms of doing first-ever developmental accomplishments. It's a dramatic result, and honestly, I would have never thought Angelman could get treated, but now I feel it's going to be treated, and we're excited about to be part of that. The UX701 Wilson program, Pinnacle platform in the clinic. We had great data in the animals, but you never really know. And our first cohort data was so exciting, and particularly for Eric and also Sam Wadsworth, who was the originator of that program.
We just had to lay it out for you. We weren't planning to put out cohort by cohort, but we decided it was too exciting not to say something about it because we've been bursting with the excitement as they've come off their chelators, and it looks like they're distributing copper again. So the potential now to actually treat Wilson the right way, restoring copper distribution as well as getting rid of toxic copper, is exciting, particularly in context of Alexion moving, Alexion AZ moving away from their chelator, which we felt was never gonna be better than old chelator. It's just another one. I think it opens the door to us to be the leaders in the Wilson disease treatment area, and I think the data we have is putting us on good track. With the low dose working, we have, you know, great safety so far.
We're in a very good place to having a great treatment for Wilson. So we look forward to both updates on OI phase II next year, Wilson, and the rest of it. So we're on a pathway to profitability, too. So let me, I think there's one more, which is our Catalyst. So Catalyst, we've shown today the facts or data. We'll have some more phase II data coming, which will be year-long data, essentially, and we'll let you know where the phase III is and what's happening with phase III. We've given you the extension data today on GTX-102. We've promised you expansion data for at least 20 patients through at least six months in the first half of next year. It should be a nice, substantial piece of data.
It would be more reflective of the dose that we'll be using in phase III, and we expect that to be a very successful update. It's going well so far. UX701, you heard Cohort 1 data. We'll have Cohort 1 through 3 and the dose decision in the first half of 2024, DTX401 unblinding. And if that's not enough, we also have MPS IIIA discussion with the FDA. I've been active in the policy front. You've seen me writing editorials. You've seen me advocating at FDA. We're making progress. There's a lot of move in Sanfilippo space and other MPS-CNS space. Breaking that door down, opening it up, opens up gene therapy and other treatments for the brain in a lot of inborn errors. It's why it's so important. Peter Marks is aligned with us. We're gonna make that happen.
We're gonna push them on this and get our program through, but hopefully do more than just for us, but for the whole field of treating these horrible rare diseases. So that's our update for today. We can go into Q&A. Thank you for coming. Ready?
Hi, Whitney Ijem from Canaccord Genuity. Excuse me. On the Pinnacle platform, for the producer cell line, have you said or can you talk about what type of cells? Is that just an adapted 293 line, or is it a different cell line that's there? And then on the Wilson's program, exciting update. Any thoughts on the first patient, or any kind of characterization you can give on that patient or the treatment, in the context of the results presented today?
Sure, I'll touch on the Pinnacle PCL cell type thing, and Eric will give a brief comment on the first patient. So the Pinnacle PCL cell line is a HeLa cell derived. That's been known. We've put that forward. It's not necessarily an original line. It is a line that's been through years of evolution and selection and so forth, but it is derived from that line. The 293 lines are actually very difficult to turn into producer cell lines, and there are certain cells able to do it and others not. To carry the AAV genes in your nucleus puts a burden on a cell to do it right. That's what the tricky part of developing. There can be other lines other than HeLa, but that's the one we're currently using.
I don't think there's anything else you have for that. Okay. Eric, briefly, what's happened to the first patient?
Yeah, so, you know, dose one, cohort one, so we certainly don't need to see a home run with all five patients. But the truth is, we did see biomarkers start moving in the right direction. She was able to start tapering, but we are still using a prophylactic course of steroids to control the increases in LFTs. She wasn't able to tolerate the side effects she was having with those steroids, so we found out afterwards that she really wasn't taking her steroids. So I think we may have lost some transgene there. We'll continue to follow her over the long term, but, you know, I think it does still stress that, you know, we do see these elevations in LFTs, and controlling that response is important.
Yeah, I think the response to the level is not really that high, but it was some. But, so far, actually, the safety has been excellent, so I think that's that one patient. There's always one, but we're excited to seeing four out of five at a low dose because our target dose was really the one or two E13, so we're excited about that. Next question?
Hi, this is Michael Riad for Jeff Hung in Morgan Stanley. Quick question for Pinnacle PCL, to what extent can the platform accommodate large-size gene deliveries? I think you had mentioned UX810 for Duchenne. Is it able to take, like, the full length dystrophin? Thanks so much.
It's AAV. Yeah, so AAV has the limit, you know, the 5 kilobase kind of limit, so you can't do full dystrophin. So there is a limit. We're our program with a micro dystrophin, it's actually one we licensed in from another company, but it's, it's doing micro. The solution for Duchenne, I think micros clearly have a role in helping, and actually one product approved, but looking bigger is gonna require more innovative approach, more innovative. Yes? Okay. We've got it. All right.
Yeah, just a few questions on the, on the Wilson's program. With those four patients that did have an initial clinical response, was there any correlation between the reduction in standard of care, medication, and the reductions in the copper biomarkers? And then on the manufacturing, can you comment on what percent of the Wilson's market you could supply with the PCL process? Thank you.
Sure. I'll let Eric, you want to do the Wilson thing and maybe manufacturing.
Yeah . So I think it's fair to say, yes, there's a correlation, but there's almost a little bit of a forced correlation because we need to see those copper biomarkers moving in the correct direction to start titrating. So yes, we do, but, you know, it, it is important to be seeing these, these biomarkers moving, you know, prior to starting tapering, and that, that does drive tapering as well.
Regarding the Pinnacle PCL platform in terms of ability to treat the market, if you recall, the Wilson's is not the APEX process, and so we do have another arm, sort of lever to pull if we needed to grow the sort of efficiency of our manufacturing process. So at this point, using sort of the rough numbers we have now, we should be able to cover most, nearly all of it.
Even with the current process, already commercial grade, COGS are excellent. We can, better than other programs. In fact, the Wilson program COGS are about 80% of the other program COGS. In fact, the whole Wilson program costs less than the other programs because the manufacturing is so much cheaper. So even at the current process, the COGS are excellent to go commercial with. We could dial it up one more step if we needed to, to get another fewfold more productivity.
Here.
Gena, yeah.
So maybe follow that question. You, you just come at 80% of the cost. I think, you know, HEK 293, if we're using, say, Roctavian dose 5 × 10^13, estimate cost is like $200,000-$300,000, but that was the numbers stated out there. I'm pretty sure every company has a, you know, very specific numbers there. So is that the baseline you are talking about when you're saying 80% of the cost?
Yeah, Roctavian, remember, is the bac.
HEK293
baculovirus.. Yeah, the baculovirus is very-
Sorry, sorry.
Yeah.
Maybe I should use DMD as a better example. That's HEK 293 adherent cells and 1E14.
You're saying they're spending $200,000?
Roughly. Yeah, 200-300. That was the numbers out there.
Yeah, I'm.
Yeah
I'd be surprised if that's true. Well, I just thought that there was, like, a billion-dollar contract manufacturing deal that was done to support that product, so I'm not sure how that lines up. But anyways.
Yeah.
She's asking 80% off of what?
Well.
She's looking for hard numbers.
Well, I think I did give a hard number, roughly hard number, at least less, for the Duchenne program. I, I do believe we should be comfortably underneath $100,000 per patient, with similar dosing as, I think it's 2E14, if I'm remembering right for-
Okay, like in terms of a manufacturing cost, there are numbers?
Correct.
Okay.
You definitely have to know how much GC you're talking about, right?
That's right.
The indica tion is important.
Yeah, it's tied to the dosing and all that stuff, so.
Okay. Second question, very quickly, on the Aβ42, that was very impressive data, selective degrader. Although I think that PPCA does have other activities as well, right? The MNAs and also the esterase. So have you done the whole, say, protein, you know, profile to analyzing what other proteins did or did not get affected?
Well, you don't really have to, Gena, and I'll tell you why. 'Cause its enzyme's only active in the lysosome. It doesn't matter what else it might cleave, 'cause it's in the lysosome, and it works at acidic pH. So wherever else it is, it's not gonna do anything. So only if the protein's in the lysosome can it cleave. When it gets secreted, as I was saying, it's secreted and retaken up, it's in a proenzyme form, it's inactive. When it gets secreted from an overexpressing cell, it's secreted with a pro piece on there. That gets taken up by the mannose phosphate receptor, taken in in the lysosome. They cut off the pro form and activate it. Because of the lysosomal activity, it's less of a concern that you're gonna digest everything. It's similar, for example, look at Brineura for BioMarin as TPP1, right?
It's an enzyme. It's in a proenzyme form, and they inject it in the brain of kids. They put 100 ml in there, right? Huge amount of enzyme. It's a proenzyme form. It doesn't digest anything until it gets into a lysosome and activated. So only proteins that would be accessible to it are cleavable. Does that make sense to you? So you wouldn't worry about sort of, emulsifying people's brain or something for that reason. But it's a question. I mean, can you, does it harm you to have too much? I think we're talking about several fold more, you know. Maybe it's eight to 10-fold more, but the amount of the enzyme that's in your body normally is not very much to begin with. So 10-fold more seems like a lot, but it's actually, on absolute terms, not a lot of enzyme.
Most of the time, for example, on those histochemistry things, naturally occurring amounts of PPCA, you couldn't see on immunofluorescence . It's not enough enzyme to see the signal. You see it only when it's overexpressed. So, we don't think it's a problem. I think if you look at the mice at the end that are highly expressing, they're fine doing it, right? So, I don't think it will be a problem, but it's an interesting question. Next.
Hi. I just have two questions, maybe one on DMD, since we've been tangentially talking about it. Emil, I just wanted to get a sense of where you guys are in development. I know it's still preclinical, but how does the current landscape potentially determine when you would enter the clinic?
Depending on if Sarepta does or does not get approved? Obviously, there could be a big advantage simply on, way of manufacturing, but, you know, theoretically, what could be some additional advantages, not just to Sarepta, but to anybody else that's in the clinic? And then maybe to go back, I'm sorry, to Angelman, I forgot to ask you earlier about what your thoughts might be for the Ionis program and how yours might be differentiated from, from theirs, and if you have a sense on when their data.
Sure.
Might be coming.
Well, we're still encouraged with our Etienne program. We have produced the producer cell, so we can, we have the ability to scale, and the APEX thing that Dennis talked about is being applied to that program. So we can get the productivity way up and get the cost control. So that part of the story is completed. We've been working on some other parts. We have some very interesting targeting work we're doing in collaboration, which I think will be the next step, which we won't talk about yet, but we're excited about. Our whole strategy on Duchenne was never to be first. We knew someone was, they were gonna be first. The point would be to come in and actually leap to the next level of efficacy.
'Cause I think the efficacy, while I think it's acceptable, I think it should get approved, 'cause some kids will never have another shot, but that shot to save their lives, 'cause once they get past a certain age, their muscles are not gonna be able to recover. We do think there's a lot of room for improvement. And thinking less about the prevalent population, think of it more as an incident population of new boys being born. The thing I'd also talk about is the $3 million price point or that range, how many countries in the world are really gonna be able to do that, right? I think gene therapy should be for more than just U.S. patients with commercial insurance, right? That there's something wrong with that, right?
The Pinnacle platform puts us in a position of actually being able to do something large scale and global. So I think there's plenty of room, plenty of room for improvement. It's not our usual thing, by the way. We're not normally going. We have to go after first-evers. In this case, we thought we had a better idea, and so far, we're making great progress on the CMC side. With the addition of the targeting piece, I think we'll be in position to have a better product. We'll talk about it when we're ready. Oh, yeah, the Ionis program. Well, the Ionis patented region, which was the original patented region, where Roche is also, that region is further the three point where we are, and our view of that region is it's just not as potent as where we are.
We've made ASOs from that region, they're not as potent. Ionis is using MOE version. When we've made MOE versions of ours, they're 10 to 100-fold less potent. They're just not as potent. So while the LNA types that we use have more risk of toxicity, the potency is so much greater that the therapeutic window difference matters, right? The truth is, if we're working at the 5 ml to 14 ml range, the chemistry won't matter. If we had to go up to 100 or higher, then we'd have a problem. Right now, where we're working, we're a very good therapeutic range, and it's so much more potent than MOE that right now I couldn't see any reason to go to that chemistry. So right now, we're not concerned about Ionis. I think we're in control of what will happen in Angelman.
If we get our job done, I think we'll be the first Angelman ASO. Next question.
Hi, my name is Austin. I'm with Joon Lee at Truist. On the Duchenne program, you mentioned that it will be a microdystrophin. Could you elaborate on the nature of this molecule? For example, does it contain the nNOS domain? And then back on Setrusumab, you know, growing bones need both resorption and formation to accommodate growing organs like the skull for brain and rib cages for the heart and lungs. Do you think long-term use of Setrusumab is safe in growing children, or do you think there might be a time limit? Thank you.
Okay, so for dystrophin, the version we are in does contain an nNOS binding domain. It is the same as the Solid Biosciences' version, that microdystrophin. That's partly we said, getting to the space that that looked like the best microdystrophin. The nNOS, clearly in MDX mouse, provides much better long-term function because your muscle doesn't work well unless it induces blood flow at the time of muscle activity, right? [audio distortion] ultimately in the dystrophin story. On the question, to choose, your question was, if your resorption important in growth, would there be a safety issue in having driving growth? What I'd say to you, what's happening with the Setrusumab is I would look at these kids as having a dial on anabolism versus resorption.
Their dial is set too much resorption, not enough anabolism. We're basically dialing it up. It doesn't eliminate the ability to have resorption where it's needed. It does not. The anti-resorption effect is modest. It's not like bisphosphonates, in fact. Bisphosphonates, in fact, probably are too strong in anti-resorption because that means there are times when you do need it. So if you have just the Setrusumab on board alone, I think you'll dial up anabolism, but you don't eliminate the ability to have important resorption. The question people have said, "Well, could you cause excess bone to be made?" Certainly, it's possible, and our view on the bone is we look at BMD over time. We've talked about this with PIs.
Once kids are achieving near normal bone mineral density and their fractures have stopped, we can back off on the treatment intensity to go every two or every three months and create a maintenance regimen. Our view right now is to work the maintenance regimen on an individual case basis to develop that regimen. We'll be looking at our phase II patients and make that call, and be the first patients we'd probably switch on to a maintenance regimen to see how they work and monitor each kid and try to learn from an adaptive individual design rather than trying to do parallel group analysis. With the phase III patients, as they come off, we'll have a chance to look at maintenance dosing.
But I think that would be the smart way, is once they get to enough BMD to get the clinical effect we need, then back them down to a level that would get what they need. But I'm actually not concerned about unsafe resorption. We're not driving it so hard that that would cause that. But right now, we keep watching for it, of course, as always.
Another question? Was there one?
Hi, Priyanka again for Anupam Rama at JP Morgan. I just had a scientific question regarding the PPCA beta amyloid i nteraction. Is there more color on the MOA in the sense that is it increasing phagocytosis within the cells to lead to the intake of the beta amyloid? And is it almost, I would say, like, is it almost dose-dependent, where if you have more PPCA, does that lead to more increased beta amyloid intake?
Yeah, so what I think is missing is that the beta amyloid is actually getting in the cells already. It's just coming in, killing cells, going out. It actually is coming into cells through autophagosome type approach or just adhering an endosomal uptake. So I think you're seeing it being taken up. It's just not effectively being processed. So we're not, we're not opsonizing, increasing. What the monoclonals do is they do bind it and help it go in. But what the monoclonals have to do is induce macrophages to be activated, to acidify their lysosomes, to make their ability to digest the amyloid. So in order for the antibodies to work, you have to induce inflammation, which means you have to get close to the area risk in order for them to work.
In fact, if you don't have an FC region, just getting them in the macrophage won't work. You have to turn on the macrophage and turn on the, the inflammation. So it's always a dance between too much inflammation and enough inflammation, right, to get it to work. In our case, we're loading the cells to clear amyloid that is ending up inside. We didn't do anything to bring it in, and the enzyme does not do anything regarding bringing amyloid in. It's coming in on its own, except this time it's staying particulate, not forming plaque, not killing the cells, 'cause we're starting to digest it when it gets in. So that's what's different. There's more information we can look at on the sort of turnover of amyloid, but it's clear the plaque itself, people say, is not problem.
The plaque is a source of amyloid that then contributes to uptake inside cells, right? So think of it as a source of a toxic co-fragments that are, what are causing the problem. So that's the way we would look at it. Is that it? Very good. Well, I thank you all for coming. Hopefully, you've had a great day learning about the latest OI data, Angelman data, Wilson data, pinnacle platform, and maybe a little bit of Alzheimer's, for excitement. Just in case you weren't expecting, tell your friends. I feel, look, Ultragenyx is at an incredible inflection point as a company. I've shown you six late-stage programs, the most productive company in the business, and, we look forward to your support going forward. We try to treat as many kids as we can. Thank you.