Good morning. Thank you so much for joining us. Really pleased to have with us Emil Kakkis, Founder, President, and CEO of Ultragenyx. Emil, perhaps we can start here by just outlining how you think about the strategy for the company going forward and what we may see from the pipeline over the next 12 months.
Well, I think the company now is an established commercial company with five approvals and four products globally, launching with a steady growth in revenue, crossing $500 million this year. So I think we're in a good place from building a commercial business. Now, layering on top of that, we have probably one of the richest pipelines in rare disease, laying out data in a number of different programs. Of course, the big program, Orbit and Cosmic, fully enrolled phase III, coming out with some more phase II data later this year. And then potentially going to interim or final assessment by the end of the year and sometime in 2025 for the phase III study.
We think the data we've seen so far in OI has been spectacular in the sense that the reduction of fractions is far greater than anyone thought it would be possible for OI. I think it changes the mindset of what's going on in OI. These kids, while they have defects in collagen, they're not making enough bone. If we just fix that part of their problem, we can change their lives. I think the doctors have seen that, and that's why we're able to enroll. The Angelman program is the other big program. We've had good phase II data read out in April. That program is coming to an FDA meeting. We have good conversation with the FDA.
We feel very comfortable about agreement on a primary endpoint, likely Bayley cognition, secondary endpoints, including Multi-Domain Responder Index and the other four domains, and likely doing a 120-patient randomized study with likely 48 weeks length. So that should get straightened out, and we hope to start that phase III by later in the year. But in addition to those two big programs, we've read out data for UX111 for Sanfilippo gene therapy, showing good data, and we'll be reading out information from regulatory meeting about the possibility of filing for accelerated approval using the biomarker. We've made a lot of progress with the agency on that. Secondly, we read out phase III data from GSDIa, which showed p-values of statistical significance in reduction in cornstarch and hit two of the three secondary endpoints as well.
We feel like very good results. Of course, it's a blinded study. We think as patients continue to get treated, they will have further reduction in their cornstarch and continued improvement, as we've seen in the past. But we're happy to have a phase III study completed. That's two gene therapies, and successfully completed this year. In addition to those, we certainly have the Wilson program, read out some early data, and that's continuing. We expect to have full three- cohort data later in the year, as well as OTC is fully enrolling phase III.
When you look through a pipeline like this with two large programs like Angelman and OI, I think in a very good place, phase III, late phase II, combined with two likely fileable gene therapy programs, puts us in a strong position to have something on the order of three BLAs in a period of a little over a year. That's not done very often, and fortunately, in Ultragenyx, we've been relatively experienced at filing BLAs, but even three at once is a challenge, but I know the team's up for it. But it puts us in position, as we think, going from 2025 to 2026, of launching multiple products, globally, in addition to the basic commercial. I think it'll turn the corner into, I think, a very special place going forward and being one of the, you know, most productive rare disease biotechs.
As you mentioned, you know, there's a lot of interest in setrusumab for OI. Help us understand or contextualize the phase II results and that we've seen to date and how to think about the read-through to the phase III program?
So the phase II results showed, looking at the median, a 67% reduction in fracture frequency, but surprisingly, a large number of the patients had zero fractures, right? And so the median fracture rate was zero. And that was kind of surprising to people, you had that many people not fracturing at all. The question is that sustained, does that continue as you continue to watch these kids? And the other part that was quite as surprising for many people was the fact that the patients were physically transformed, too, that they're able to start doing things they weren't doing. We showed a kid who'd been a little bit longer on treatment, who stopped using wheelchair and walker and started running around. People who'd been in a car accident or fell downstairs and didn't have fractures anymore, right?
So they're having a girl who loves sports and stopped playing, and now she's gotten back and playing. Of course, it creates some risk if they start playing sports. And someone asked me, "Well, is that going to be a problem?" I said, "There's no way in the world I'm going to make someone feel good so they can play sports and stop them.
Yeah.
You just can't. But I'm actually not worried about it because if bones are stronger, they're going to do well. And the more active they are, the better, the more strong the bones will be because your, your bones get strong by exercise. When you lay in bed, that you actually get weaker. So we're pretty excited about the profound improvement in fractures because they've not had anything. And bisphosphonates is a competing treatment, are 20% at best, fracture improvement. They're not really solving the problem. So context is, this is the first time they've had a transformative treatment, and the doctors who felt that you had to fix collagen are finding out that's not really true, that the inadequate production of bone is at the core of what's going on. So we'll put out some more data on how they're doing.
We'll just give you a sense of how they're doing feeling longer term as we treat them? Do we maintain the high fracture reduction rate? You know, what does the bone mineral density do? And that data will give you at least a readout how longer-term treatment goes. In the phase III, we'd expect by end of the year, early next year, that the first interim will be evaluated, and if not, then a second interim. That was a 0.01 for stringency, and then 0.01 for the second interim, which is a few months later. And then if that doesn't hit a few months later, would be the 0.04 for the 18-month assessment. So I feel very good. I think we'll end early, but I don't know for sure, right?
But I think based on the size of the trial, and the fracture reduction we're seeing, we should. It highly depends on how many fractures are happening. That part's hard to predict. How many fractures are happening to the people enrolled? Are they going to be more careful?
Mm-hmm.
Or by being in a trial, will they inevitably have more fractures because they're transferring, they're going to the hospital, they're doing stuff they wouldn't have done? Sometimes that gives you more fractures. So we'll see how that goes, but the number of fractures will suddenly will determine a little bit how much power we have and whether we end early or not.
Can you just speak to that with regard to the phase III study design, the powering assumptions, and your expectations around the two interim analyses, the probability you assigned to it, kind of hitting on that first or second one?
Well, we're assuming that the fracture rate was, you know, around 1 per year, and we've assumed the 50% for the powering decision, and the 150 is adequate size for trial as defined. We put the interims in because instead of 50% reduction, it looks like it's 67 or higher, which would make it possible to get to power than an earlier time point. And I think the hardest thing to know and trying to judge probabilities is what the fracture rate is and what the exact percent reduction. It also depends a little on what the mix of patients are, because there are Type I's, Type III's, and IV's. Type III's and IV's have more fractures, are more severe, lower bone mineral density, potentially bigger ability to move, right, and improve. So the mix will have some impact.
I think it's a little hard to predict. We've said less than 50% chance of finishing on the first one, but I haven't said exactly what the number is, because I don't really know the number precisely. But the idea of the interim is to say if our assumptions are wrong for the trial and things are way better than we thought, can we end early, right? So it's a little harder to know what that percent should be. But right now I'm feeling I think we've made the right decision. The FDA has agreed to those interims, which is good. They've agreed that we can stop early if we hit 0.01 on the first one and the other two. So I think they're on board because I, you know, I think that the results are important and impressive to them.
They've never thought very much of bisphosphonates for OI. They made that very clear to us. They think they're not good for bone structure. The mechanism of anti-sclerostin is really a much better mechanism. So I think the FDA is on our side here, so, we're encouraged. I think there's a possibility, but I still put it at less than 50%.
You spoke to, how there could be fractures just because of how active, you know, these individuals become. How does the FDA think about that in the context of quality of life? Because that has to have some value here.
It's one of those things you're not going to get credit for because we can't quantify it perfectly well. We have anecdotal information, but we're not quantifying exactly how many sports everyone's playing. It's a little hard to do that. And how do you relate someone who's playing lacrosse, you know, versus something else? So we have a volleyball player. We have a volleyball player. So it's one of those things that parents are gonna know, right? Families trying to make their decision are gonna know, that they had a friend who went back and is doing great, and they wanted to get that, too. So it'll have an important impact at launch. Just like in Crysvita. Crysvita, patient to patient, was very, very important.
They want to know, and we had, for example, a lot of little girls who were starting to do gymnastics, and they could never do them. They talked to all the other moms with the little girls who want to do gymnastics, right? They all found out they could do it afterward. So, so we started getting all these videos of kids doing gymnastics. So that's how it propagates. I think in OI it'll be similar. People see what's going on with their families, that'll help drive it, but right now it's been pretty exciting to see people doing stuff they couldn't do before. And sometimes it might cause a fracture, but you know what? The better they live than have an occasional fracture, 'cause right now they're not. They're sitting at home. They're just alive, but not living.
Could you speak to the launch strategy here, or how you think about commercial footprint? You know, recognizing that you have an existing sales force behind Crysvita.
Well, it's as good a leverage as you can imagine, because Crysvita and the XLH and OI doctors are 90% overlapped. So they know us, we know them well. We'll probably launch with a very similar plan that we started with Crysvita, which was around 36 reps, dividing the states into 36. We'll have patient diagnosis liaisons that will help identify patients around those centers to feed the funnel of patients. A lot of OI patients are going to major centers, but there still will always be patients who are living with their disease out and about, and we want to make sure we find them more often than the once a year they might go, or once every two or three years they go to a center. So the patient diagnosis liaison piece will still be an important part of that.
It really helped Crysvita to maintain its trajectory for a lot of years. Like, linear, it never didn't plateau; it just continued linearly. So, right now, even the team that we have working with Kieran in the field, we have a team of 20 in the field. They're still finding patients, and they're still, 50% of the scripts are still coming from new doctors, new patients, 50%. So it's clearly an important commercial effort, right? If half the scripts come from finding those people. So everything we've learned from that will set us up for OI and hopefully maybe do it even better because we learned on the fly. We had a plan, it was a good plan, and we continued to adapt, but I think we're as well set up as anyone to launch the OI.
I think the one thing I would say about OI is it's more urgent, it's more serious than even XLH, and there's a little less, like, affection for bisphosphonates. Whereas in XLH, there are a lot of people were comfortable with oral phosphate. We had to get them out of that. But in bisphosphonates and OI, I don't think there's comfort. I think people do it, but I think our effect will be larger. I think this is why we'll help, and I think expect it to launch better, even than Crysvita, which launched extremely well.
How large is this commercial opportunity in, in your territories?
Well, if you go to the major clinics in the U.S., most of the clinics will have 50% more OI than XLH patients. Our estimate on the population is around 60,000 in the commercial territory, so that includes Europe, but within the U.S., it really looks like the big centers have much more OI than XLH. It could be OI is just better diagnosed than XLH. XLH is a little, can be a little more difficult to diagnose, whereas fracture is, right, it's easier to pick up as being part of the OI. But so we think it should be a larger addressable population, more readily accessed than it was with XLH.
Perfect. Let's switch over to Angelman syndrome. You've recently shared a data update and initial regulatory updates. How does this data inform your view of efficacy and the next steps here?
The Angelman data in April really told us that we can take now a set dose and treat a large number of people and see the same movement we saw, and that in some endpoints, it was even faster and better. So it gave us great confidence that we can replicate the experiment with a whole new group of patients, a whole number of new sites and places, right? And get very comfortable results. At the same time, when we look at the patients who are on drug for more time, they continue to gain ground. Over a year of continuing to gain ground.
So it gave us a sense not only that we could have a better response with the higher loading doses that we're using now compared to the earlier, but that we can actually see continued progression during the whole year, which tells you that going for, for example, a 48-week study, would have benefit by being able to separate the groups even better over time and ensure that we have the power. So I think the replication, the increased speed of response, and the safety gave us confidence that we can do a study now at phase III.
Could you touch on the adverse events that occurred and, you know, prior to the protocol amendments and how concerning or not concerning they may be?
Well, they were certainly concerning in the beginning when you see significant lower extremity weakness, weakness in the first five. But we learned a lot since then, and now we're more confident and reassured that this is a manageable problem and not a, not a, not a problem that's going to stop the drug. Out of the 53 patients, we had one, I call it a half. The other patient had a response that was not noticed until almost afterward that they had it. So with only one or one and a half out of 53 who received all the loading doses, it tells us the frequency is way less. Second, it was mild, mild, mild, moderate at most, but relatively fast. Within a few weeks, it got better, so it wasn't like the first five. It took more time.
Thirdly, patients all want to stay on the drug, and if you had that event before you got back on the drug, you could be successfully treated without having it recur, which means that having an event is not an end of therapy. It's just something to manage. We think it's about... It does tell us that technique matters, and we do have to train well, but we feel comfortable now. This is a manageable problem, not a big problem. It's reversible, it's milder now, and it's not an end of therapy for anyone. The FDA's response to us was fine. You know, filed. They're not asking for any more information. We've done all the heavy lifting on what, what is going on, and I feel pretty comfortable now. This is more like a localized chemical irritation of the drug sitting in one spot for too long.
In all the cases, even the recent ones, they had the same local inflammation. So fundamentally, the drug must have been sitting there too long. Whatever we said... That's what happened, 'cause you can see it on the MRI. So we just need to reaffirm for people that they need to do this technique the right way, and if they do, they get the benefit without having that effect. What's important, though, beyond that particular lower extremity weakness, is what else is happening. We have a very clean safety profile otherwise. We don't have any of the other things that people have been seeing, none of the kidney issues or platelet problems or severe headache problems that others have observed when you give a lot of intrathecal ASO. So, I feel good about the fact that it's one thing and it's manageable.
This is one advantage of having a very potent drug that works at 5 mg-14 mg , is that you, you lose a lot of the other side effects that relate to the chemistries of the ASOs and puts us in good position. With Roche bowing out and still unable to find a partner, which means there's issues, right? With Biogen opting out instead of opting in, and I'm sure Chris Viehbacher would have wanted a, a large neural product that fits with the Spinraza franchise, right? The fact he didn't go means it wasn't as, it wasn't as good, and in some ways, Salveen, by putting out our data, we essentially were challenging others to show us what they've got. I think Biogen kind of, Biogen, who could clearly outmuscle us in the commercial field in neurology, decided that they wouldn't do it.
So I think it puts us in position in Angelman and, the position I thought we would be in, which is the science that Scott Dindot did, was the most potent and smartest of science. He's figured out something no one else knew, and that's opening the door to a really potent new therapy for Angelman syndrome, and we're the ones with it.
At your midyear end of phase II meeting with the FDA, what are the items you plan to gain alignment on, and what would be a, you know, a best case outcome for you and a likely outcome?
Sure. We feel pretty comfortable that getting alignment will not be difficult because we've already had some pieces. We already talked about a 120-patient randomized placebo-controlled trial. They already know that, and that was fine. What we need to settle on is primary endpoints, secondary endpoints, and length of trial. But we know from the past that 48 weeks is probably fine for them, and that's the number we're probably gonna go with, which is day 331, but 48 weeks. Since there's a linear and continued improvement in separation going a little longer, in other words, 48 weeks instead of 32 weeks or something, just gives us more power and more time on safety. So I think FDA would like that. So 48 weeks is one of the key questions.
On the primary endpoint, I think they're more comfortable with the psychologist-administered, validated product like Bayley. They're a little more apprehensive about patient-reported endpoints, and we will have some of those, but they'll be more secondary. And so based on what we've already heard, that's what we expect. MDRI is a new thing for them. They're more uncomfortable with it, but we think we can build it in as a supportive secondary. They'll help establish the by-patient totality of the data effect to support the primary. So that's kind of what we will settle: primary endpoint, length of study. We'll also ask the question, how to support the other indication. The main study will be for the 80% population, which is the deletion type. The question: What about the missense and UPDs and others?
We think some of the smaller populations, we'd like to support with an open-label design because we think one high-quality randomized in the severe population will prove cause and effect of the drug. Therefore, we can support the safety and labeling by just studying the other groups in open-label basket-type trial. We have to get some read on whether that's doable or not. It may not be one conversation with them, but our goal in putting forth one primary, large randomized trial is to say that is the anchor for efficacy, and the other stuff will be supportive, and we need not put multiple different types of Angelman patients through placebo-controlled trials, right? See, it was a big deal for these families.
I've been talking to them for a while, but I think it's necessary to do one good one to end all questions, and we'll support the rest with others. So our goal would be to file ultimately for the whole indication and not for just one type.
How hard will it be to manage patient variability, just given the heterogeneity of this population within a placebo-controlled trial?
Well, one of the key ways to manage variation is to stick to the deletion population. So that's why we're doing that. It is 80% of the population, but the deletion patients, from a natural history standpoint, do not improve. Therefore, that's one of the big variables, is what's happening with the placebo group. Now, someone has told me: Well, how do you know Bayley doesn't have a placebo effect? We did. In fact, Investor helped us chase down a couple studies, and the one study was a levodopa study in Angelman that had the Bayley. And the Bayley, in that study, showed only a 0.8 point difference over 48 weeks in the control arm. Right? The treatment arm didn't work either, so the point being that there was no placebo effect, essentially none. It was the same as natural history.
That's not so surprising, but if you can't have a placebo effect, which involves you to make up cognition you don't have, right? Just 'cause I feel like I might be treated doesn't make you wanna think smart all of a sudden, right, make good questions. I guess people think there might be bias in it, but the truth is, it was, it was a zero. So we're, we're very comfortable that by sticking to deletions, we'll keep the study clean. And if you have missense or varying degrees of enzyme levels, those are variables, right? That will be harder to control, and it'll create more noise. So that's part of the reason why we're designing it this way. We're designing it, prove it in the severe patients, a consistent population, demonstrate it, and then look at other cases and show them before and after.
That way, each patient is their own control, and you don't have to deal with between-patient variability. So there is a particular design choice in doing it that way.
Next, here on the gene therapy in Wilson disease, can you frame expectations for the Stage 1 data expected in the second half and how you're thinking of validating the efficacy profile?
So what we're hoping to see later in the year would be what three cohorts data look like in terms of urinary copper reduction, standard of care withdrawal, and, you know, their ability to sustain their copper control without standard of care. We showed some early data suggesting some improvement in standard of care, and we'll be mainly looking at those urinary copper, standard of care removal. Now, the third thing that's important to us is copper-loaded ceruloplasmin or ceruloplasmin oxidase activity. This is a measure of whether copper is getting loaded on ceruloplasmin at what level, because we think that's part of the potential benefit of gene therapy over chelators. So those will be the three things we'll look at. The goal would be then to design. Are we at the right dose? Which choice is the best dose from a safety and efficacy standpoint?
Then head into phase III. We've already agreed on the primary endpoint being urinary copper with FDA, but there certainly could be things we would adjust looking at it, depending on what we see in this data set. So, but the thing that's important is the FDA has agreed to the idea that copper management as an endpoint is appropriate, and therefore, we're not dealing with things like neurologic scores or other things, which would be very hard to do because people ask us, "Well, what about neuro scores and things?" That... The problem with neurology in Wilson is that some patients may have irreversible symptoms, some may have reversible, so they're all mixed up, and only a fraction of them will have those problems. So it's very hard to power a study, right? We're talking about a 60-patient study.
You can't power a neuro study with 60 patients, really. So we're gonna look at case examples of neurological problems, see if they improve. But in the end, the whole study has to operate on managing copper distribution and reducing the need for standard of care.
At the same time, you have the GSDI and OTC gene therapy trials progressing here, one which is heading to a regulatory filing.
And UX111 on Sanfilippo.
Yeah.
So earlier in the year, we ran out Sanfilippo data, which looked excellent. And we just ran our GSDIa. I think both those are potentially filable gene therapies, and we'd expect to be talking to the agency later in the year about filings for both of those. The GSDIa data, as we expected, the 48 weeks, shows the group separating beautifully, but the true clinical outcome will take more time to involve as patients continue to wean starch. In a blinded format, they didn't wean as much as you'd like because the patients didn't know they were told by a doctor, who was told by another doctor, not what the result was. It's a little hard. I mean, taking medical action, but not telling you what the result was because you take it. So it's a little trickier.
Once they go to open label and people know what their results are, they'll be able to deal with it a little better. But we're happy to see the powerful results, so I think it shows that the drug really works. And GSDIa, commercially, is a much more urgent disease than, let's say, Heme. It's more urgent because these patients are taking six or seven glasses of starch every day, every few hours. You don't forget what you're on, right? Every few hours, you're drinking a slurry. It's like 300 g of starch, so this is a pound. You can imagine, [Charlotte], right? Someone, drinking a pound of starch as a slurry every day. What you feel like? You feel terrible because like you have Type 2 diabetes, they're hyperglycemic all the time, and they're making insulin. So it's like they're in... feel terrible.
Plus, they're always scared because they got to remember, they gotta take it with them. They gotta take it, when they gotta take it, and wake up at night, got two alarms. "If I miss, I might die." You have to kind of get in the mindset. I tell people it's like living with a gun to your head, and you and as long as you keep drinking your cornstarch, it doesn't go off. But if you forget, the gun goes off, right? You have to understand the mindset situation. When I talk to moms taking care of their kids, as they're describing what was going on, you could see them start to tremor. It's like they have a PTSD response of the adrenaline, of thinking about their kid, every kid, every, every day, every day, every few hours, every few hours, right? This is very urgent.
It is not just getting rid of the cost of cornstarch, it's about relieving from the fear that any moment something could happen, you could die. And so that's why we think people want to enroll in the study and enrolled well. Same is true for UX111. The child is gonna die if they don't get treated, and they don't get treated early. It's a very urgent... It's a lot more like little guns than SMA in a sense, if by age two, you gotta get treated.... And we've shown if you treat it early, you have a very nice result, and nearly all the patients have an excellent result. So those two, I think, will commercially do well. They're not as big as some of these other ones, but they'll do well. They'll get utilized, and so we're excited to bring those forth.
Just a last question here on how you think about business development, but also how you're thinking about the cash runway, you know, recognizing you will likely get PR filings.
Partly because we raised the money recently, but we also have a growing revenue base, and that puts us in position to be on track to going profitable by 2026. Some of that contributes from the newest products. There are multiple potential PRVs in there, so that will certainly help us. We are looking at other business development deals that potentially as part of the thing. However, we're very averse in general to licensing out products commercially. Just historically, I've learned that the global commercial value is really best kept. In giving up territories, you give up a lot of upside. So if you notice, most of our programs, we have full rights. Ones we don't are ones that someone else had before we got them.
So we are looking at our technology base and the license we can do there, but we'll want to consider what we'll do and be opportunistic on cash. We could potentially go all the way to profitability without raising cash, but don't really want to go too low. We want to have enough working capital. And we do have other business ideas and things we need to do, so we're going to look thoughtfully at being opportunistic on managing cash. And I do feel like we can see the light end of the tunnel here in terms of getting through and getting to profitability. We've been very diligent on cost control, headcount controls, to allow our revenue to catch up and put us in a better position. But I feel like we're in a very good spot, but we'll be opportunistic as we move forward.
It's exciting to be close to the end of that period where you're completely in charge, and if you imagine OI launching Sanfilippo, GSDIa launching, right? By the time the Angelman's coming, we'll be in a quite a different place, right, as a company. And I would say there's very few companies that have as many prospects of fileable products in hand as we do.
Great. Well, with that, thank you so much, Emil.
Thanks a lot.