Welcome to the Morgan Stanley Global Healthcare Conference. I'm Jeff Hung, one of the biotech analysts. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. For this session, we have Ultragenyx with CEO Emil Kakkis. Welcome, Emil. Thanks for having me, Jeff. So for those who may not be familiar with Ultragenyx, can you provide a brief introduction? Sure, Jeff. Ultragenyx now has been, well, it's been in existence for 13 years, and we've 4 approvals and 5 programs in late-stage development, and I think of entering a period of multiple important catalysts for the company. Our program in osteogenesis imperfecta, setrusumab, showed phenomenal, bone mineral density improvement recently, and we'll be talking more about that program and fractures, which are an important part of osteogenesis imperfecta, at our Analyst Day on 16 October 2023. Our other programs, we have three gene therapy programs, GSDIa, OTC, and Wilson, that are entering important stages of their development. And we have probably the program most people are interested in, which is the Angelman program, GTX-102, which will come up to an update at the 16 October 2023 meeting, where we'll talk about the extension patients and the changes they're observing and their clinical meaning for this. We'll follow that up with expansion data on a larger data set in the first half of 2024. We also have a gene therapy program for MPS IIIA that we acquired, and as a company, I think we've managed to build a strong gene therapy franchise, and I think there's a lot of room for AAV value in treating human genetic disease. But in addition, the ASO treatment, GTX-102, or traditional antibodies, are places where we can gain value as a company. And I see us as continuing to grow our commercial business and a series of catalysts in the next six months, and potential multiple approvals going forward will put us in position to be one of the leading rare disease companies in the business. Great. Well, let's start with setrusumab. A few months ago, months ago, you mentioned that you reported data from phase II/III study. So can you just talk about that study and remind us of what you saw? Yeah. phase II/III orbit study had 24 patients in a phase II portion, which allowed us to look at dose, whether we're going to dose it 20 or 40 milligrams. We reported data showing that in this disease, osteogenesis imperfecta, the patients at baseline have a, they have a defect in their collagen, but they also have a more fundamental problem, which is they don't make enough bone. Their bone mineral density was -2 Z-score, which means they're at the 5th percentile of the population of bone mineral density. So that's how weak their bones are. We showed that giving them setrusumab, that they had a massive increase in bone mineral density, essentially about 10% in only three months. The good news about that, it said that the patients with osteogenesis imperfecta have bones that are ready to start making bone. If you simply stimulate them in the right way, they'll start making bone, and we think that will translate into substantial improvement in bone fractures. So we're impressed with the speed and the magnitude of the effect that we were seeing. We didn't see that much difference between 20 and 40, which kind of said, "Look, once you turn the system on, it doesn't matter. Trying to turn on more doesn't really matter. Turn it on, these kids are ready to respond." And that's... We just wanted to make sure that we didn't miss efficacy, and we're pretty comfortable with the 20 dose, which was the easier way to go forward. So we will be putting out more data on those patients now through 6 months and/or longer and looking at fractures. We said at that time, as the patients had improvement in bone health, bone health meaning the appearance of fractures, bone pain, and functional activities, like how they were doing, which told us that patients were doing well, and we're pretty encouraged. But I think there's a lot of interest in the Street on the exact effect on fractures, and we'll be talking about how this cohort of patients' fracture frequency changing over time between the first month, let's say, second month, third month. And that'll allow us to give you kind of a sense of what the fractures are looking like and a little bit more about the overall bone health. So we'll be putting that data out. The trial is already into the phase III portion. We're enrolling with phase III, and it's moving along well. Our expectation is to get close to finishing enrollment, if not finished by the end of this year. That program then will read out between 1-2 years, depending on how many events there are. With regard to another program we have, which is the COSMIC trial, that's the younger patient trial, that's head-to-head with bisphosphonates. That trial is also initiated and ongoing. That'll give us a placebo-controlled trial where we can show the fracture benefit in a wide range of ages, improve the efficacy of the drug, and as well as the effect on symptoms. The other trial will help prove head-to-head against bisphosphonates that setrusumab is a far better treatment, and we're very comfortable that is true. Bisphosphonates have a 20% reduction in fractures, but our expectations for setrusumab will be at least 50% or greater fracture reduction. Maybe on that last point, on, like, what are you expecting for the IV bisphosphonates? Yeah, the historical data, there have been five randomized trials in OI, and they had only two of the five studies were actually positive, which tells you the treatment effect size is small. The treatment effect size was about 20% reduction. But people are using it because there's nothing else. So it does seem to help how patients feel about their bones. The bones feel better, which is probably because it's reducing some level of microfractures. But the problem is, there's probably too much resorption in OI, but the bigger problem is they're not making new bone. When you make new bone, that's how you strengthen bones. Preventing resorption can help the bones a little bit, but what they really need is to lay down bone where the bones are weakest. The way the bone production system works, whenever you turn on the bone-making machinery, it always lays down the bone where the bone is moving, where it's unstable. So that's why the anabolic effect of setrusumab will be the right effect to strengthen OI bones, and we're encouraged so far that this is exactly what they need. That even if you have a mutated collagen, we can make their bones substantially improved in strength and improve their bone health without necessarily fixing their collagen defect. Maybe taking a step back to the phase II data that you spoke about. So then how are you thinking about those results in the context of fracture rates for the phase III portion? Well, we didn't report any fracture rates in phase II, but we did show the bone mineral density effect of 10% approximately. Mm-hmm. in 3 months. Now, that level of effect should be sufficient already to improve bone fractures, based historically on, on, you've seen in other trials. So we think we already have a bone mineral density improvement magnitude. I think the question people ask is: Is bone mineral density predictive of fractures? Because there have been some situations, particularly with not anti-resorptive agents, where fracture frequencies or bone health was not optimally changed, but not in the case of anabolic agents. Those things that make more bone, those have consistently shown that bone mineral density improvement by the bone anabolic pathway will strengthen the bone. And so we're confident that we'll see that predictive value for the bone mineral density we did observe. Great. And you mentioned the COSMIC study. Maybe you can just talk a little bit more about this study and what you hope to see. Well, in our view, the great potential for setrusumab is to take a 2-year-old or a 1-year-old who has OI and prevent their spine from degenerating, prevent them becoming wheelchair-bound, chronically in-pain patients. If we can help their bone strength, prevent the fractures that deform their bones at a young age, we can have a dramatic effect on the future and make this standard of care. So getting young patients, that it gives us an opportunity to look at all fractures, including the spine, and to establish how much this will change a young kid. Now, in that trial, we're doing it head-to-head with bisphosphonates, because in many centers, they are already putting them on bisphosphonates, and putting them on placebo at a young age was a challenge. We look at that as an upside, though, because it'll give us head-to-head data, which will be very important in Europe and in some territories to know that here's this thing that people are being given, and that your drug is way better than them. So it's... We'll look at superiority in terms of the fractures against bisphosphonates. So that is that basic study. It's a 2- to 4-year-old randomized, controlled versus bisphosphonates. It should be in the 60-70 patient range, and based on the very high fracture rates in that population, it should be more than adequately powered to look at reduction. Given that these patients are younger than those in ORBIT, how does that affect the bar for success on fracture rate? Well, with more fractures, it's easier to detect the change. So some of those kids can have 8-10 fractures a year versus 1-2, right? So 8-10 fractures a year just gives you way more ability to detect a difference if it was 50% versus 20%, let's say. My hope is that the difference is gonna be bigger than that, but I think there's plenty of power in that study. That's why it doesn't need to be as large. Mm-hmm. Great. Well, maybe shifting to GTX-102, can you just remind us how many patients are currently on drug and how enrollment is progressing? And are you on track to enrolling the 40-50 patients that you've mentioned in the past? Yes. So there are a lot of different groups of patients that are on the drug currently. So there are 3 patients from the original 5 who are being redosed. And we will talk about those in 16 October 2023 as well, about how they did before and how they're doing now. There's a group of patients that were treated in the U.K. and Canada, that are part of the cohorts 4 through 7. Though, that cohort group is around a dozen patients, 11, 12 patients, that have been on drug now for more than a year. So that group of patients will talk about how they're doing. They've been in the maintenance phase, and they've been titrated. There is, so that's that, those two groups. There's an additional 7 patients that were in the U.S. that are also being treated. Now, those 7 in the U.S. have been converted onto a high-dose regimen or loading, and that's going, and we have now opened up the expansion, which is cohorts A and B, particularly, which are multiple ex-U.S. sites, not just U.K. and Canada, but multiple sites, including the ones we'd expect for phase III. And that's enrolled more than 20 patients already in that segment. Adding it up, it's quite a few patients now on drug. I haven't put it all the numbers together. But we'd expect to have the extension patients talked about in on 16 October 2023, with the redosing and the expansion patients, which we pushed out in time to get to 20 patients worth of data, mid first half. Twenty patients, we think, will be loaded at a certain dose level. I think we'll provide the Street a stronger view of what this looks like, and will put us in position for initiating a phase III next year. You kind of touched upon this, but... You know, since you harmonized the dose ranges between the U.S. and ex-U.S. cohorts, any update on activating U.S. sites that were on hold? Yes, so we are activating U.S. sites and several coming on now. There have been, of course, the first site at Rush has been extremely efficient, and they've already converted their 7 patients onto the new load regimen, and then there are a few, what we call cohort C and D patients enrolled in the U.S., and those sites coming up. Some of those will not contribute to the 20 that we're talking about, but will contribute to the broader 40 patients worth of data that we'll get. And these patients from the, this phase II, as a group, 50 patients, something, will become kind of the long-term exposure patients, so that once a phase III is completed, we'll have, these patients will have at least another year of exposure. That allows us in discussions with the FDA or other regulatory authorities of what's the longer-term safety and maintenance, and that's what these patients will provide. So, that's where we are on that. So for the data update in the first half of 2024, can you just talk again and clarify, like, how that relates to your expectations for the phase III to begin next year? Like, how, how does it not impact or- Right. -the timing? Well, in our last meeting with FDA, which was a type A meeting to get open, we already talked about running a 100-120 patient randomized controlled trial, placebo-controlled trial. That part was already kind of agreed to as the basic plan, and that one trial would be, should be enough to drive the approval. And in addition to that, they want us to talk with COA. We're gonna be talking with the Clinical Outcomes Group, and the division agreed also to talk with us about endpoints 'cause they recognize the endpoint story is complicated, a lot of different choices. So we'll have those discussions along the way. When we get the 20-patient data, that will be a point where we'd go and an end-of-phase II meeting. But the end of phase II meeting should be to complete the discussion on endpoints, not to initiate it. And our hope would then be to convert into a phase III trial, which should be designed by the first half, but hopefully initiated in the second half. These days, I would say to you that a lot of clinical trials are being hampered to some degree by the post-COVID health care systems. A lot of the PIs have lost staff, and the whole healthcare system's under strain, and so we have to find ever more creative ways to help support sites so they can conduct the trials we need. But this is one where we're planning now, and the way we designed the phase II was to give a lot of sites at least a patient or two in phase II to tee them up, to get their site prepared, train them on the endpoints. So when it's time to turn them on for phase III, they all are phase II experienced. That's the concept, 'cause we knew this trial was more complex. We needed to have sites that already have hands-on instead of being, for the first time, getting involved in intrathecal therapy and a neurodevelopmental disorder. So by setting up all those sites in phase II and scattering some patients, allows us to essentially pre-train phase III sites, get contracts, understanding of how to contract and budget with each of them. So our hope is all that's about teeing up phase III to go quicker. So if you need to modify the protocol based off of, the data update, you know, meaningfully relative to what you had been expecting, I guess, is there much buffer built in to remain on track to still start the study in 2024? The main thing that will happen when we get the data is we're gonna order the endpoints. Okay. We're not gonna be doing new endpoints. The endpoints will have been developed. We're just gonna order them and get comfort from FDA that they agree to that ordering. We'll then talk to other regulatory authorities, but that's the only thing that's gonna happen because the trial design otherwise, including its length and its size, will be pretty set. So I don't think there's a lot of variables left. It's really trying to order and decide on how we're gonna look at five different domains in this complex disease. But to turn it into a simple story is this transforming Angelman- Mm-hmm ... syndrome into a disease where patients can actually gain ground and learn how to communicate and learn how to do other things in life that they've been unable to do in the past. And we think the treatment will be transformative, and we'll continue to figure out those pieces. We'll also learn a little bit more about maintenance dosing with time, but the maintenance dosing won't affect the phase III exactly, so we have a little time for that to kind of optimize. And I would also point out that all neurologic disorders like this, in the end, in the long-term commercial setting, will require some level of optimization on an individual basis. Because you're talking about ages 2 or 4 to 17 or potentially adult. To think that's all gonna be, you know, one dose and one situation is just not right. Our hope would be to establish a load range and a maintenance range and give people the tools on how to optimize each kid's care. Great. Let's talk about the Analyst Day coming up next month. You talked about this at the beginning and actually in some of the other responses that you had, but can you just remind us of what to expect from the event? Well, first of all, we haven't held an Analyst Day for a while. We've generally put together strong events because we have a lot going on, and I think it's a great opportunity to give investors a deeper dive into the basis for who we are and what we do. And I think these days it's harder for investors with the strain and stress of what's going on to be able to open their sights to more than one program. So this is an opportunity to lay out more of what we've got going on. We will have an important section on osteogenesis imperfecta. The timing of the Analyst Day relates to the ASBMR, which is a big bone meeting going on in Vancouver. So that's the timing of it. That's why it's at that point, and we'll be releasing the bone update data. So that'll be an important piece, and we'd expect to have some investigators talk about how the drug's doing, as well as what the data are. We'll talk about Angelman as well. I said extension patients, as well as redosing patients, hopefully give you both a sense of how much effect we're seeing and, and as well as how it's clinically meaningful for patients. We're gonna talk. We'll have a high-level view of the clinical stage of gene therapy programs, and then we're looking at diving deeper in a few of the other programs that we have going on, which we haven't talked as much about. And we'll find, finally decide what that list will be, but at the time. But there's a number of programs that are moving along, including one new program people have never heard about, that I think will be pretty surprising and exciting. So that'll be the reason to stay to the end. So for GTX-102, you've said that the data will be more high level and focus more on clinical meaningingfulness, with less quantitative information. Can you just clarify, like, what we should expect to see around? Well, we get a lot of requests from the Street, and there was concern that the quantitative data wasn't as understandable, what the numbers meant, and so we were trying to emphasize more clinical meaningingfulness. Of course, as soon as we said that, everyone said to me, "I want more... Well, what about the quantitation?" So it was, like, no way to win. It was, like, one or the other. So we'll try to provide a broad update on how those patients are doing, including some quantitative scores, including clinical meaningingfulness, so just see what we're seeing. It's a phase II program we're learning, and I think what I can say to you is the drug is working. I think it's safe in this regimen, and we have said all along that it was way more potent than the Roche molecule. Roche pulled out because the truth was their molecule wasn't potent enough to achieve efficacy without having significant other side effect issues. I think in the ASO world, all the drugs that work are the ones that are really potent, right? When they're really potent, then you can do something neurologically, you can't do any other way, right? That's when they're valuable. But if they're not very potent, then you get all the other chemical toxicity issues with the ASOs, and then they're not as great a drug. So we're talking about having efficacy in the 5-14 milligram dose range, which is pretty close to where Spinraza is, around 12. So I think that gives you kind of a sense. When you're in that range, I think it's when you see the kind of efficacy that's really important for patients. So this all relates to the underlying science of the GTX-102 program, which is where we're targeting, which is a separate patented area from where Roche and Ionis are. It's further five prime, and the importance of being further five prime is that when you clip the transcripts that are coming from the end of gene strand, at the very beginning of transcription, they derail the transcription just completely. It's far more potent. It's an important part. It's in the paper that Dr. Dindot put out, that termination transcription is far better when you clip near the five-prime end. So this understanding of the human structure of the gene and how to target, it seems esoteric and arcane, but that is how we made the decision to actually do the project. Because the only way to be better than a company like Roche or Biogen is to have tremendous experience in neurologic space, is to know something that they didn't know about the gene transcription. In this case, Dr. Dindot did have that information, and that gave us the confidence that the science will win out, and we'll have a drug that works. Great. Maybe a few questions on the pipeline, or other pipeline programs. Next year, you'll be reporting initial data from UX701. Can you just walk us through the design of that study and what we should expect to see from the interim Stage I data? And then if you're able to show initial signs of activity, what would be clinically meaningful? Yeah. So the Wilson program, I think, has gained greater interest now, particularly since Alexion pulled out, because there's all this feeling that maybe greater chelators is all you need in a copper disease like Wilson. What I've been saying from the beginning, before that happened, that Wilson disease has been thought of as copper toxicity, but truthfully, it's copper toxicity overlaying copper deficiency at the same time. The copper is in the wrong place. It's also missing from the brain and other places. That complexity means just chelating more is not good enough. You have to start to deliver it if you really want to improve efficacy. And Alexion's story kind of said they had a better chelator, but it didn't actually have the effect that they were hoping for, and they pulled out and dropped it. Since we're giving a transporter back, we have the opportunity to deliver copper. So the design of the study, there's three cohorts at three dose levels of 5 patients each. First cohort was completed. We have early data, and we released some information about it, saying that it was safe. The cohort passed the DMC cut. We did not have any significant issues. We're doing very traditional AAV. This is AAV9, but we're talking about liver doses, right? Relatively low doses. And we were actually seeing signs of improved copper trafficking, meaning copper not going to the urine and copper coming into the bloodstream through the other pathway for its delivery. So we actually see the signs of the improving copper trafficking, which I think was encouraging us at the lowest dose. We're in the middle of cohort 2. That should be completed. It's a doubling of the dose, and then there's one more cohort of 5, where another doubling of the dose. Our expectation is we would go up to the highest dose. If the highest dose is safe, we would do the highest dose. Because we're using the Pinnacle PCL platform, our COGS on this program are 80% reduced. So as long as it's safe, we'd want to get maximum effect for what we hope to be a single-shot therapy, and to get the max amount of copper loaded on the ceruloplasmin, which will help reverse copper deficiency, which we think is underpinning some of the symptoms in Wilson disease. So after this phase II five patients or cohort, we'll make a decision on dose and go right into enrolling phase III at the same sites. Efficiency of the phase II/III design, you've seen now several of those from us, OI, and others. The value of this is the sites are set up, and so when we make the trigger to go to phase III, we don't have to start this process of contracting and regulatory discussion and everything else. There's no dead time. What we've learned, though, is doing placebo-controlled during that phase II part is hard, so this is now open label. But it's a biochemical, so we can look at the biochemistry and get quantitative assessments of what's going on. The phase III trial will take 60-70 patients to enroll, but we're assuming with good data from the phase II portion and with the dropping out of the Alexion AZ chelator, that there's a lot more interest in what we're doing here, that there is maybe a better way, and I think that will help us get that trial enrolled. But we're encouraged so far in Wilson, and we think there's a potential to be a, have a transformative effect for Wilson disease. We're, we're not in the business just to replace chelator drugs. We're in the business to transform disease and treat them in a way they've never been treated. And I think when you treat a disease like this by the correct method, you discover something about the disease you didn't really know. In this case, it's not just copper excess, it's copper deficiency at the same time, and gene therapy will allow us to show that. Great. You're also expecting phase III data from DTX401. Can you just remind us what you need to see on reduction in oral glucose replacement with cornstarch while maintaining glucose control to be considered positive results? So in the GSDIa program, these patients are on 300-400 grams of starch per day, and they're taking it as a slurry, like 8-ounce liquid slurry, every 2-3 hours or so. Imagine doing that. Now, people say, "Well, it's just cornstarch." It's like, they think of it like a dessert or something. It's not. Patients hate it, but the thing you have to understand about the situation is, it's not just the cornstarch, it's also the gun to the head. Because if they don't take it and they go low, they could die. So you're taking starch, but you're always afraid. You're always thinking, "If I go low, if I go low, I might die," right? Think about living that way. If you talk to some of the parents, you can tell, man, they have been adrenaline-fueled, like, their entire child growing up. Like, that every time they mess up, they do wake up at night, the kid could die, right? So you have to understand that, because if you talk about clinically meaningful, I want you to understand that setting, what that feels like, right? So if you bring down the cornstarch need 80%, and the patients realize that if they miss, they're not gonna die, you've taken the gun down. Now, whether... It takes time for them to adapt their metabolism. We're seeing it takes 2-3 years for them to fully adapt, but we think a substantial reduction, and particularly some of the ability of them to sleep through the night and not die, to have control, that their liver actually produces glucose output. Each of the patients are null, so they have no output, right? So the truth is that that is what will be transformative. What we've seen is with the level of reduction we're seeing within the first 48 weeks, that that's a transformative effect, and that effect was large enough that we had great demand to get in the study. In fact, we had people clamoring to get in the study, and then we ended the enrollment, and it had some countries that took too long, that didn't get involved in the study, who were very upset. But they took too long. I thought, "Well, they should go faster next time instead of dragging us through the mud," like, unfortunately, too many of the countries do. So fortunately, we, the study will—I think—will show a percent reduction that's, you know, 50%-80% reduction is a change of life because now you're not gun to the head kind of dependent, right? You can listen to some of our verbatims. I can go work out, and I'm not gonna crash. I don't have to bring starch with me everywhere I go. Some of them were starch free during the day. They're taking a little more in the light. We also learned, though, that their metabolism is so messed up by the starch, it takes time for their insulin—they're making a lot of insulin—to reduce. Now, this insulin, you think, would be weird. Why would a patient with hypoglycemia make so much insulin? It's because they've been feeding themselves with starch, so they've been overdoing it, driving their glucose up to keep them from the edge. But at the same time, they're driving insulin production, so their hormones, their, their, beta cells, as well as their cortisol, are off. And so it's taken time for them to actually get settled back. In the first cohort, it's out, like, three years or so. That's when their hormones actually finally get more straight. That's because they've been on starch for, like, 20 years, most of these patients. 20 years, you train your body, you know how to be. So we're encouraged that even, you know, 50%-80% reduction in starch during the trial will be predictive of a substantial improvement. It should get lower with time, is what we've seen, as their metabolism, their other factors get better. We'll have other scores, functional scores, and that will help us characterize that, but the effect wasn't subtle. For regulatory authorities, cornstarch reduction didn't seem like a hardcore endpoint to them at first. But then they also checked with patients. They found out that actually the patients think it was... So it's one of those things where you have to kinda educate. The FDA held a listening session. The patients told them, "This is really important," and FDA changed their mind. That's why they allowed that endpoint. At the EMA meeting, they brought a patient to the meeting after we presented what we're doing. They said, "What do you think?" He said, "I totally agree with them. This is really important." They were surprised. They thought the guy was gonna tell them something else. But we talk to patients, this is part of our thing. We know what matters to them, and being able to be free of the risk of dying is what is the change for GSDIa, right? If you think of it that way, then you understand what the story is about. The story is about having some ability to be glucose self-sufficient and not to be afraid that one momentary error is gonna result in something horrible happening. Great. Well, we're over time, but maybe one last quick question. Sure. Maybe like 30 seconds or less. What do you think the Street most misunderstands about Ultragenyx? That we can have a pipeline this broad and generate value, and that we can do it with a high probability of success, and that we're pretty capital efficient, given we have a significant burn, but we also have more products than I think anyone out there. It's hard for the Street to fully appreciate the true value of all that, but we do. I think with time, if you look at the 2013, 2014 IPO class, how many companies have four approvals from that class? And not that many, right? No one. We're the only ones I'm aware of. And how many of them not only have four approvals, but have five late stage also in hand? That part is the efficiency of our ability to find stuff, put it into play, drive it ahead, fight the timeline, make sure it goes, is important. So I think people have to see that broader value and fundamental story that is probably, I think, one of the top tier rare disease companies, and I think what will be a legendary story our first 20 years for sure. Great. Well, looks like we'll have to leave it there. Thanks so much.