Okay, I think we're gonna go ahead and get started. Thanks everybody for being here. My name is Chris Raymond. I'm one of the senior biotech analysts at Piper Sandler. Pleased to introduce our next presenter, which is Ultragenyx. Emil Kakkis is with us, the President and CEO. We've got about 25 or so minutes for a informal Q&A, just to go over the sort of the format. I'd like to keep this as informal as possible. So if anybody in the audience has any questions, just raise your hand, let me know. I'll make sure your question gets asked and answered.
Before we dive into Q&A, Emil, for the folks who might not be completely versed on the Ultragenyx story, maybe just walk us through the elevator pitch, if you will, and then I'll dive into my questions.
Sure, Chris. Happy to be here with you again. Ultragenyx is now 13 years in from founding, and in that time, we've built a next-generation rare disease company. We have four products generating $420 million-$450 million revenue this year. We have five late-stage programs, three phase III gene therapies, as well as an Angelman program and osteogenesis imperfecta. They're both large market opportunities for us. It's already an important inflection point, growing revenue, heading toward profitability, but also putting in play a large number of high-value, rare disease products coming to launch. I think looking at anywhere from 3 launches -5 launches in the next 3 years -5 years, I think we're in an important inflection point for the company, heading toward profitability, and I think the best rare disease pipeline in the business.
Awesome. Okay, so maybe we'll just sort of go stepwise through the commercial push/pulls, and then we'll jump into the pipeline. So maybe just on Crysvita. I know the Q3 print was a little lighter than maybe people were expecting, negatively impacted by a one-time decrease in channel inventory. I think it was Kyowa Kirin's change. But, you know, are there any other sort of challenges or headwinds, Emil, that we should be thinking about, you know, moving forward?
I think Crysvita is actually doing really well from a demand perspective. So with more people in the field, with us, our people and our Kyowa Kirin partner, who's taking, took over commercialization in April, we have more people in the field. And if you look at the start form generation actually was stronger this year. So demand is there. They're taking over. There were some changes in the NDC product and pipeline, but that stuff we think is all temporary. We also have had very strong fourth quarters in general. If you look at every year past, a lot of catch up happened in the fourth quarter. So we felt good, reiterated guidance on Crysvita, and I think the product's doing well. I think the part that's also important is our Latin American business continuing to grow.
The pace of start forms this year was as good as it was last year in the U.S. So we're, you know, we're at 500+ patients on treatment and growing in Latin America. So I think since we own that business for quite a long time, I think it's gonna be do very well. We're also starting to get revenue from Turkey, which we also manage.
Mm-hmm.
So I think CRYSVITA is strong. I think our partner is doing a good job, and we're collaboratively working with them in the field and getting it done. It was expected to have some temporary things, but I think the question is: Is there demand? The demand is strong, and we feel very good about the product.
You know, sort of a last-minute question here. Today, there was some news from NICE. I got a few questions from some folks on this decision. You know, it was not exactly a rejection, but just maybe contextualize the news from the UK and NICE that came out this morning.
Which news are you talking about?
Did NICE have an opinion on if they got that wrong?
Well, Crysvita got passed by NICE.
Yeah
... the first time it went by.
Yeah.
But that was a while ago.
Okay,
Was there another opinion?
Yeah, I guess I misunderstood. All right, so-
Yeah
... Evkeeza, I wanted to quickly follow up on, touch on that. So, you know, a couple of weeks ago, we saw an EMA update on the label to include HoFH patients five years and up, but, you know, sort of help us think about the launch moving forward.
Yeah. Well, we spent the last year kind of starting the launch sequence, and then there is a sequence in Europe, picking countries, which countries you start and all that. So we've been working through that sequence. This, 2024 will be where a lot of HTAs will be ruling, and we'll end up getting price negotiation. We've negotiated some prices. We've started launch in Germany, and so it's picking up now. I think the really important part of the 5 segment -12 segment is because a lot of those kids can't really do apheresis.
Mm-hmm.
A lot of adults are in apheresis, but you can't do apheresis two times a week on little kids.
Right.
So this drug will be far better for really little kids. So there is an important segment where we can pick up patients. We have already been doing compassionate use. There are kids 5 years old that have cholesterols over 1,000, who are gonna die, you know, by the time they're teenagers. Those are high and in need. This is where this drug is gonna be superior to anything they're on, and the reductions of 50% you see in the trial on top of everything, doesn't tell you what happens in the most severe, like double null types. Those patients got a 70% reduction on top of everything, right? So there's no drug that's more potent than Evkeeza.
So that younger segment, I think, will be the preferred option, and I think that will help galvanize growth of the product because everyone that's tried it finds the reduction is within a couple of weeks of starting the drug, and it's always on top of anything they're on. It's. And there are very few LDL drugs that work on top of everything, right?
Right.
And so we're really, I think the drug is gonna be a really important drug for HoFH, and it's clinical HoFH, not just genetic. Clinical, meaning all the variation of genetic types, not just LDL receptor homozygous, just to be clear in the labeling in Europe.
Mm-hmm.
So that's a little bit larger population. We're excited about it. I think it's a really good product. I think, Regeneron did an excellent job in creating it, and the younger patients, I think, are opening the door to a, you know, stronger launch, I think.
And so maybe, I know you guys haven't provided, you know, any 2024 guidance at this point, but just as we think about the, you know, specific programs, how do we think about the commercial setup in the next year? Especially with the transition, you know, you know, your, your reps on Crysvita are, are, you know... There was an extension there, and there's a transition that, that,
Right
... is gonna be finalized. Just what, what's the setup?
Well, the transition is continuing to operate-
Yeah
... and it's possible that some people will be persistent afterward. We do have the right to promote to medical genetics even after the end of the transition.
Mm-hmm.
But we're working with our partner collaboratively. We may have still some people helping promote during, after next April, so it may not end. We're talking collaboratively what it takes and what the benefits are, and I think so far it's helped. I'd look at Crysvita continuing to grow. I think all of our pipeline has been growing in the 20%-30% range. In that range is kind of what we're expecting, and so that's where we'd expect. We usually, what we usually have done is put the guidance out at the beginning of the year.
Yep. Okay. All right. So the pipeline. So Angelman, obviously, been a major topic of discussion for some time now. I know development here is, you know, it's top of mind among investors. You gave the phase I/2 extension date cohort data in at your Analyst Day. I thought it was impressive. The next update is mid-2024 first half 2024. I think you gave very specific timing around that. Just remind us, you know, Emil. I know you've had a number of bites at the apple in terms of... Or we have. You've provided in terms of data, but what should we expect to see? What's the setup? And I know there was some delay there, but maybe walk through that decision.
Sure. Well, we had a large number of patients that have been on drug for a significant amount of time that went through a low dose starting dose and titrated during loading as well as during maintenance. And that's the group of data we put out, just to show you what happens over 504 days of treatment. And what I think was important to show you is that even starting at a very low dose load and titrating up, we had efficacy that was, I think, exciting, changing their lives, really. Fundamentally changing their lives. You looked at the type of things we showed. We tried to show some videos of those that were in the room for that meeting.
We showed walking to show you how their walking has improved, that these wide-based, unstable gaits become narrow, and you could see how kids could feed themselves, or they couldn't feed themselves. They can understand their name and follow instructions. They couldn't understand language at all, but if you call their name, they wouldn't understand you were talking to them. They couldn't understand. But imagine how a child that doesn't know how to interpret any language can hear instructions and actually follow instructions. For many parents, it's like their child is suddenly a real child, whereas before it was almost like having a, you know, someone who's like an animal that they, they couldn't really talk to, they couldn't understand them. And so they really...
It's been, it's been quite transformative, and if you add up all the various domains improving and put them now in the same kids that we show using the MRI, the heat map approach, it allows you to see all the different domains and all the different patients. You can see why this is a transformative treatment. Now, we delayed putting out the expansion data. What the expansion data are, we used the first part of the study list to titrate patients and figure out what's a good, safe, and effective dose. So we said, "All right, we've got an idea about dosing.
Let's go ahead now and treat a whole bunch of patients at that dose for one that's gonna be for phase III and see what that shows us." We just wanna verify what is, what is data that would look like, a phase III look like in terms of side efficacy. That data, we didn't want to go out with eight or 10 patients worth, and so we held off because it turned out if we held off another couple of months or so, we would end up with 20 patients of data. Just that's how the enrollment went. 20 is just way better than 10, eight to 10. We expect to have 20 patients of data that have had at least day 170, all right, about six months of treatment.
We'll have probably 10 that have gotten to day 254, and this will give you a better sense of the dose effect of the higher doses that we're using. And so I think we'll, we'll put that data in context. Between now and then, we expect to have our meeting is scheduled with the FDA. We'll have a meeting to talk about endpoints. The FDA has been very open about having just a separate meeting to simply talk about endpoints alone, which is good. It's encouraging. It means they're, they're leaning forward with us into the next step. And there are a lot of endpoints, and many people complain about the complexity, but let's look at- I look at it as a positive thing. When you have multiple domains improving, this is a meaningful drug, so if there's confusion, it shouldn't be.
We have so many things we can measure that work and a change. To me, that's, that's a beautiful situation, and we're looking at using a multi-domain responder index, a way of capturing efficacy across five domains, because it's a far better representation of what's going on in the disease, and it, it gives weighting to all the different things that improve. And sleep, for example, improving is very important for some families, but not all of the kids have trouble sleeping. But for those that do, the sleep alone is transformative for the kid and for the family. For other kids, walking was their issue more than other things, but having communication, having better behavior on top of all that. If you put that together, that's the way to characterize Angelman, not any one domain.
So we'll have that discussion with FDA, and when we come out with the data, we'll have at least... We'll have made progress in that direction. And our expectation then is to set up for an end-of-phase II meeting, where we have a more finalized plan that we can turn into phase III quickly in the second half. But we're, we're excited about the Angelman program, and Roche has pulled out. Biogen has put out-... a little bit of data, but since we presented our data at Analyst Day well before that, I think if they had better data, they would have put something out, but I don't think they have it. The truth is, the region of we're targeting for our ASO is far more potent. We showed that with Roche. They didn't, they didn't have the potency, right?
Mm-hmm.
So what we said was correct, and I think the same is gonna be true with the ASO. They're using much higher doses, and I don't think they'll have the same potency. Both those products did work, do have some effect. So the mechanism works, but I think we're in the best position of having a highly potent molecule, and that's what's gonna differentiate us.
Just maybe to clarify, you mentioned having met with the FDA to talk about just endpoints, and then you'll have your date, you know, set-
We'll release, yes.
Early, early in the year, and then your data in mid first half. Will you be able to articulate what that phase III development plan looks like at the time of your data, or is it after the end of phase II meeting? What's the sort of sequence so that-
When-
Investor will know what to ask for?
Yep. When we show you the data, we'll have some concept of what phase III might look like, and we'll try to present the data in, in a format that looks like what we might do for phase III. I don't believe our meeting with FDA will finalize the endpoint, but we'll have a good feeling for what direction to go in, and we'll try to use that as a launching pad for just putting forth what our data looks like. Because I know what everyone wants to know is, from that data, is this a study that can be powered and be successful in phase III? So we'll make sure to put that together in such a way that people can interpret it.
Okay, so you highlighted your multi-domain responder index at your Analyst Day. Maybe just talk about the validation work that's required for this index. You know, is there any sort of validation work, you know, for the-
Yeah
... that needs to be completed for MDRI ahead of the registration event?
Well, let me explain one thing about MDRI. It's not really... It's really a composite of different endpoints. The endpoints are validated individually, like the Bayley receptive communication has a lot of validation behind it. So each of the underlying endpoints for our domain are individual known endpoints. They're not... So if there are new endpoints, they would have to be validated, certainly. The biggest thing with MDRI that we have to do is verify what's the minimally important clinical difference. What's an important clinical difference? The magnitude of change on an endpoint that we're gonna score the win. That's what we have to provide the data to support that win and get FDA's agreement. That will be defined upfront with the agency. For the Bayleys, we are doing that work. There's a lot of historical data.
We think the MID is close to what the statistical significant change we showed, as we showed the number of five or six, depending on which Bayley you're talking about. For the Angelman severity scale, whether we use the scale or not, or we use another instrument for behavior and sleep, there's two endpoints we have for behavior and sleep. We could use alternative endpoints. We'll figure out what we need to validate, but we will need to figure out what's an important difference, so we can score it, and that will be something FDA will want to see. Now, we can do that from our own data by looking at CGI scores and the endpoint for CGIs for a domain, are you better by, say, one plus or two plus?
You can use that to calibrate how much change did they see in the endpoint and try to calibrate, hey, if you see 10-point change in that endpoint, then 70% of the patients show a +1 or +2, let's say, in their CGI score. Does that make sense?
Mm-hmm.
So there's a technique for creating and validating what the MID should be, and we'll, I have an entire team, Allie Schreiner heads, that does endpoint development strategy. So it's, it's one of the unique departments Ultragenyx has. We started from the beginning, because when you're doing rare diseases that have never been studied before, the endpoints become the biggest factor, and so that's why we created that department. So a team of PhDs who actually do endpoint stuff only. That's their own job.
So maybe just a question on safety. It seems like the, you know, your, the modifications of dosing protocol have solved the lower extremity, you know, weakness issues that you saw early on. Is there some sort of length of follow-up that FDA or, or, you know, other reg, you know, EMA.
Mm-hmm
... might be looking to have to support filing, or are they?
Well, I think it's always an important issue. It's intrathecal, so it's just a more invasive procedure than, like, a typical-
Mm-hmm
... treatment. Because of the lower extremity weakness, certainly there's an important bar we'll have to go over. Part of the reason for expanding phase II-
Mm-hmm
... some people said, "Why not go straight to phase III?" Well, part of the reason for expanding is to quickly get a large enough patient pool on therapy. So with the original patients, plus the expansion patients, we'll have something on the order of 60, 70 patients on drug that will have been on drug a year, you know, 2 years longer than the phase III patients. I think that 2 years , 3 years of data, I think, will be enough safety data. That's one of the reasons to do the expansion, is to get as much data. So while phase III is going, the idea is that phase III is, let's say, a six- month to nine-month study or around in there, that we would have enough patients with 3 years + of data to give them comfort that we do have long-term safety.
We've been very happy with the long-term safety 'cause it was a very important issue, is if we change the acute onset of this issue, but if you keep dosing them, would this problem still accumulate and come later? But clearly, that's not true. So it has nothing to do with accumulation, but it has to do with the acute inflammation, irritation of the meninges. And so very simply, putting the patients laying down and giving the flush just keeps the drug from settling in the local part of the spine, and we're able to solve that problem.
Is there any reason to think FDA might think differently about this than EMA?
... Well, FDA has been more conservative, but I will say also, since our last meeting, they have come around quite a bit on the program. They've been very collaborative, they've been very open, and the tone has changed a lot. So I'm actually feeling pretty comfortable that we're gonna go well or go fine with that. And the fact they've accepted another meeting in the middle of development even, right, which they didn't necessarily have to accept, but they came through and what they committed to, I think it's good. EMA, there are gonna be some differences for sure, but they're often very different. But fundamentally, the FDA is gonna end up defining what will happen in phase III, and we'll have to manage what EMA wants in what we do.
I would put to you that the phase III study is maybe the main, you know, pivotal study for proving efficacy, but it's not the extent of all work. We will look at doing some open label studies in some of the other subsets and to figure out ways to measure them objectively. There will be some ways to fill out the data set with some of the other information we will collect.
One final Angelman question. I know you've talked at length about the demand that you're seeing from families, you know, for clinical trial participation. This might be an early question to ask, but you know, assuming you find a pivotal path that's expedient, you get a positive readout and launch.
Mm-hmm.
Just what's the thinking around, you know, the setup for commercial launch in terms of, access to IV, you know, to transfusion, capacity, you know, training around, you know, the actual intrathecal administration, drug supply, all that kind of stuff? What's the... What are the major pinch points, I guess, that you're thinking about?
Well, fortunately for us, the launch of Spinraza has trained a large number of centers to do intrathecal ASO treatment, a large number of centers to do it routinely. That has really opened the way for us because if that hadn't happened, then there'd be a much bigger lift. So we're not that worried about the lift. There's a lot of centers that have experience, and there may be some that have to do it, but because there's a nice established set of centers that really are comfortable, the launch will be pretty easy, I think. We'll have to work on adding some other centers, but I do believe the majority of these pediatric neurologists are doing SMA, ASOs already. So that really helped us a lot. With regard to... I think it's a traditional rare disease launch. I don't think there's anything substantial.
I don't think that a very large field team is needed. I think there's a lot of awareness in the community, and there's a set of doctors or very specialized doctors who will be doing the treatment. So I think a relatively typical, lean, smaller field team-
Mm.
Specialized field team would be launching. From a patient diagnosis part, we usually have a patient diagnosis program team that also goes in the field to find patients. I don't know if that's gonna be as big an issue here because it seems like the diagnosis of Angelman has really gotten a lot better in the last years. Right now, there seems to be a lot of patients already identified, so we don't see the same issues we would have seen, let's say, 15 years or 20 years ago, where Angelman diagnosis was far less efficient.
Got it. Okay, so maybe let's transition to setrusumab. Impressive fracture reduction data from your phase II study. You know, it seems, at least in our view, that the phase III de-risked pretty substantially. So you've guided to full enrollment of the phase III by the end of the first quarter next year, I think. How much, you know, did that fracture data sort of impact the demand for physicians enrolling patients? Was it a a major determinant?
Well, I think it will be. I think the challenge with a placebo-controlled trial in this population is they are getting bisphosphonate treatment, which they would not be able to get during the period. So that is a challenge. They'd have to come off their bisphosphonate. The FDA would not let us put our drug on top of bisphosphonate. Okay, so that was the reason for this. The bisphosphonates last in their bone at least a year, but that's still a challenge going to placebo, where you have someone who's very fragile, a lot of fractures, coming into a placebo-controlled trial. So what the phase II data said to them is there was a real upside here, that setrusumab is not just like another bisphosphonate. Setrusumab could actually substantially improve their fracture reduction.
Bisphosphonates in five randomized studies have had only two positive studies, and the treatment effect size is about 20% reduction. So 57% reduction represents a dramatic improvement. The other thing that's important, if you looked at patients after six months , seven months, there weren't any patients with fractures after six or seven months. Half the fracture, even the 67% rate, includes fractures from the beginning of the study, right? First was half the fractures in the first three months, and then it was scattered. So the truth is that effect was very surprising to doctors because they didn't think that making more bone in these patients was gonna strengthen their bone that much, but that is what the mistake. The mistake was thinking that the collagen makes their bones weak, when the truth is their bones are weak because they're not making enough bone.
And if in that setting, making bone, which has a mutant collagen, but it's actually not bad bone, it's good bone, maybe not perfect bone, but it's still good bone. You could actually transform your lives and have a kid, like the one kid with Type IV, who was the longest treated, 17 months, who stopped having fractures, who came out of a wheelchair, running around like a normal kid now, who's had falls and not fractured like he used to. That's a change of life. So when you put that in front of patients, then that does bring... And the doctors, first of all, have to kind of grip the reality that they didn't understand their own disease they've been studying all this time.
I talked to them. We had an investor conference at ASBMR, and I talked to them, and I challenged them that this is hard for them. It was, like, different than they were thinking. So it's much about getting them to understand that this drug is doing something that they need.
Right.
And so now they need to kind of think about how important it is. And, they admitted this was a change of thinking in their mind of that this isn't just a little bit better. It could be much, much better. So it is gonna pick up the enrollment. Enrollment is going fine. I think we're always in all rare diseases, we always battle enrollment, right?
Mm-hmm.
Enrollment always is a battle. It's because there's, you're always trying to find patients. The challenge with this disease is that they're really fragile patients. I mean, they get fractures transferring from their wheelchair into the car and coming to the hospital. So those guys, it's, it's a big deal to go on a trial, you know?
Mm-hmm.
Now, patients are randomized two to one to drug. So the patients do have a better shot at being on drug, and if we end the study early enough, they'll all get crossover under drug. So if you're in the placebo arm or in the other arm, you have a much better shot of getting treated at least 2 years -3 years before anyone else. So in our view, it's a must-do, and we believe we'll get this fully enrolled.
Okay, great. Well, I've got a bunch of other pipeline assets that I wanted to talk about, but unfortunately, I'm getting the high sign that we're out of time. But, thanks very much for that great presentation.
Good.
Lots going on next year. Thank you.
Thank you.