Ultragenyx Pharmaceutical Inc. (RARE) Earnings Call Transcript & Summary

Good morning to everybody listening in. Welcome to the Bank of America Healthcare Conference. I am Tazeen Ahmad, one of the senior SMID biotech analyst. It is my pleasure to have with me our next presenting company, Ultragenyx. Presenting for Ultragenyx and sitting with me is Eric Crombez, who is Chief Medical Officer. Eric, thanks for making the trip over from the -- [indiscernible] not as far.

There's a lot going on at Ultragenyx. There's been a lot of questions being as I guess, two of your programs, OI and Angelman. And so not a surprise, we'll spend most of the next 40 minutes or so talking about that. Before I do that though, maybe since you've had so many conversations with folks at this point, can you just give us an overview of both the OI and AS programs, where you stand with those, and then we'll go into specifics on each, if that's okay.

Yes. I guess starting a little bit in order. So osteogenesis imperfecta for the OI, Angelman programs being our big value drivers and then also including the gene therapy programs. But focusing on osteogenesis imperfecta, we obviously did not clear our second interim analysis, and we announced that earlier in the year that leads us to full study readout. We're saying we will talk about that externally around the end of the year, and we define around end of the year at December or January. Certainly, we share the disappointment on not achieving IA2, but that wasn't a foregone conclusion. Our modeling, everything, we understand about the drug, told us that we had a good probability of success of achieving IA2. The truth is, we probably did need to do a little bit better compared to what we saw in Phase II with the caveat that Phase II with 24 patients open label, and we're trying to extrapolate that into 159 patients, 2:1 randomization. So there is some plus/minus there. I don't know it's an ongoing blinded study. My guess is we came very close, but did not hit that far. Maybe if it was 0.05, like it will be at end of study instead of 0.01 as the alpha spend there, we would have achieved that. We don't know, but I do expect we came very close. It did give us the opportunity to look at our assumptions, look at our model, look at our statistical plan and really make sure our assumptions are holding true. We have the right statistical plan from beginning to end. And everything we have done really reaffirms our expectation and our probability of success leading to full study readout and that will be all patients at, at least 18 months. We do have a hard rollout at 24 months into an open-label extension. So those patients will be between 18 and 24 months with an average duration of 21 months of follow-up. So a good period of time for this group of patients.

Okay. All right. So let's talk about the first and second interim reads for OI. It's in the past, but it's still kind of part of the conversation. So the feedback that I got, and to be fair, we had also been writing about this was that just given the likelihood of the success of a study being successful over time because you would collect more events, why was that first interim really necessary? You talked about doing the modeling and you don't -- you didn't lose a ton of alpha. But realistically, why was that a good time to take a look at the data?

Yes. So I mean, now with the benefit of hindsight and it can be very beneficial, I don't think I would have done, I want to be honest with you. I think maybe we got a little overly ambitious. And just for the context that drove that ambition and hope was Orbit's a Phase II/III study, which means we had to design the Phase III part of at the same time we designed Phase II, and that is very, very helpful. You're not stopping for end of Phase II, you're not really losing the year plus to do that and stand up a Phase III study. So it let us select a dose and go seamlessly into Phase III that saves a lot of time, but that does mean you have to design your Phase III early. And at that time, we had the ASTEROID data from the study Mario originally ran and it was on the strength and really the surprising efficacy we saw in the original Phase II data set that said, okay, we can clearly do better. We have overpowered, over design the Phase III part of it, put in these interim analysis, and we thought going from 24 to 159 patients, 2:1 randomization, maybe we could hit very early. And we were surprised how early this drug takes effect. I think for adults, we're talking about bone remodeling. For children, we're talking about bone growth and remodeling. And I think we all think of that as being a relatively long period of time and months and years. So it's not something that happens quickly and seeing results in Phase II within the first couple of months, really clear results. At that time, we thought we could have hit very early. Again, with the benefit of hindsight, it probably wasn't worthwhile. I would still do IA2, for sure. I think it is worthwhile to us as an organization to gain approval, launch quicker, that time matters to us. It does also matter to patients, and we do care. We know that patients out on placebo, patients in Cosmic randomized to just bisphosphonates are out there fracturing and setrusumab is effective than they're out there in the control group's fracturing unnecessarily. So with those 2 factors and with the probabilities of success we saw, it was worth it.

Yes. So going into the second interim, which happens late summer, I think your team was optimistic that it had a good chance of working. Now I won't ask you what your internal likelihood of success for that was. But even that you were generally bullish, did it surprise you that you needed to continue the study now to completion and what would be reasons why that would be?

Yes. So I personally was surprised and I share the disappointment. And it was interesting, we didn't really solicit feedback from RPI, the treating community and patients, but it was interesting to see that they were very much like we appreciate that you try. We're happy to go to full data readout. So it was almost like them thinking us, reassuring us that it was okay not to achieve IA2. So that was good to see. The one thing that I do wonder about, and we were also surprised in the Phase II data to see Type 3s and 4 patients responding very similar to type warrants.

Maybe just define Type 1, Type 3 and Type 4.

Yes. So to me, there's very clear [ phenotypic ] spectrum here. So your Type 1, those are the mild end of the spectrum. Those patients are fracturing with a reasonable amount of trauma. We're talking about some type of falls, something that's not really normal versus your 3s and 4s who have fractures with very little trauma or no trauma, and fractures, cause of fracture can be happened during sleep. So that's just the normal kind of twisting of your arm as you roll over that [ in fracture ]. I was talking to a patient who her and her daughter have Type 3. The daughter's most recent fracture, she's in high school was when she reached for the seatbelt, she snapped a [ long bow ]. So very minimal or no common Types 3s and 4s. They started a much lower bone mineral density, they have much higher fracture rate. We had -- and, again, in that subset of patients, a small group of Type 3s and 4s who were responding equally to Type 1s. Again, those are relatively small numbers. It will not surprise me when we see the larger data set from Phase III that maybe it does take your 3s and 4s more time to lay down enough bone, to get enough improvement in bone mineral density to stop fracturing. So maybe that's what pushed us to 18 months. It honestly may be that we came really close and 0.01 wasn't enough alpha.

Right. So the Type 3s and 4s, how do they differ in Phase III versus what was ASTEROID?

Yes. So we didn't change the entry criteria. And again, we don't like to bring untested things into Phase III. But on the strength of the Phase II data, and again, remember 3s and 4s, they can fracture transferring from the wheelchair to the car, sitting on the train or transporting to your [ sensor ] to sign consent and participate. So it doesn't surprise me early on in Phase II where they said, we will wait and see, is it worthwhile to take this risk to come into clinic and possibly fracture. But it was the strength of the Phase II data that said to them, it is worthwhile. So in a sense, in the Phase III, patients self enriched and we went from roughly 1/3 of patients being Type 3s and 4s in Phase II to about half and half being Type 3s and 4s. So it is a bigger subset of patients. They have the most benefit from this drug.

Right. So they have tactically the most benefit, but I'm just wondering for a clinical trial, just to be devil's advocate. In the context of the timing that you have for a trial, is there risk that because they could take longer that the -- I don't want to say overallotment, but the higher weighting of those more severe patients may make the timing like maybe not 18 months would be enough, maybe it would be even longer.

Yes. So we asked ourselves that question. And that is 1 thing you can do in an ongoing Phase III without really disrupting the trial is you can always make it go longer. So we asked ourselves the question, does it need to go to 24 months. Everything we were looking at and everything was telling us we don't. So we asked ourselves that question, we decided to stick to 18 months.

Can you share like how you got to that confidence? And What did you look at?

Yes. I mean, that's the thing with an ongoing blinded study as we don't have a whole lot of new information. The 1 thing we did look at in a blinded manner, the total number of fractures. I don't know where those fractures are falling. Our assumption that if setrusumab is working like it did in Phase II, most of those fractures should be falling in your control group. So you can model where those fractures are falling to tell you, are you in the right place. And then we still fall back on the Phase II data. And yes, it's 24 patients, but the results have been very consistent. We don't have nonresponders. They have responded and that response has held up. I mean, we really are looking -- at this point, my goal for them treatment-wise is to normalize bone mineral density and stop fracturing. That's what I want for these patients.

The other big, I think, conversation we tend to have with investors is how does the use of bisphosphonates impact the study. So patients have been using that as de facto treatment. Mechanistically, how are bisphosphonates working to help these patients versus how setrusumab would be working?

Yes. And I think you hear a lot of people talking about bisphosphonates as locking in bone. And I think to me, that is a helpful way of doing it because there's other people looking at PTH, which is controlling calcium levels along with bisphosphonates. And that's really trying to go after this disease at the chemical level, you're trying to lock in bone and that could help strengthen bone. I think when you look at the meta-analysis of data available on bisphosphonates, the data that other companies put out relatively recently, it's not enough to really increase the bone mineral density to a point where you're stopping fractures in a meaningful way. Our meta-analysis for bisphosphonates tells us maybe there's a reduction in fracture at around 20% for bisphosphonates. And certainly, that's better than nothing. Because to date, if you diagnose a patient with OI, at least you can offer something because as a physician you never want to say, here's this terrible disease, I can do nothing for you. So again, that's helpful. But compared to the 67% fracture we've seen in Phase II, we think we can do much better, and then we'll be able to have a data-driven conversation with the data coming out of Cosmic.

So how long does it take for the bisphosphonates to wash out?

Yes. So we can't answer that question with any precision because no one's done that evaluation. I think you may need to go to bone to figure that out. I don't think you could do it just from blood levels. I think everyone would agree that IA1, that's a relatively short period of time, bisphosphonates are not really washing at that time point. At IA2 where patients are at all at least 12 months, maybe. I think everyone would agree that by 18 months, you probably are seeing some wash out. That could put your placebo patients at greater risk from fracture and that could be, unfortunately, for patients leading to more fractures in our control group. We didn't count on that. We didn't make that power of our design or powering. We don't include that in our modeling. So from a statistical perspective, that would be upside.

Okay. So that leads me to maybe the next question, which is, can you just talk to us about the powering assumptions of the study?

Yes. And that's what we've always anchored to was the greater than 80% power to detect at least a 50% reduction in fracture rate between those 2 groups.

Because the effect size is a conversation that we're having a lot now that it's going to go to 18 months at least. I think there was a conversation about the first or second interims investors at least. We're not really talking about the importance of effect size, but I think there's an expectation now that if it's going to take longer, you need to see a meaningful effect size. So you powered it for at least [ 15% ]. What information will we see when the top line data comes? So let's say that all goes well, are you going to be talking about effect size that we've seen at the top line?

Yes. I mean, I think while we haven't 100% decided on exactly what that release will be, I think we understand what people want to see, what the expectations are. It was very important for me to land last patient for Cosmic and Orbit together because with my sights firmly set on our regulatory submissions for approval, it's easier to land that as a single package as opposed to those studies being staggered. It just gets clumsy. So I think it would make sense to talk about both studies at the same time. Certainly, when we talk about top line, to me, for OIs, it's all about fractures. You want to support that with bone mineral density. And then while the safety has been very, very clean, we never want to take safety for granted. You always want to talk about safety, too. Quality of life is absolutely important. But I think for me, when I think about what's important from top line, it's safety and the fracture rate supported by BMD.

I think BMD's connections to fracture rate seems to still be debated. I think there's some evidence that indicates that there's a correlation and some evidence that I think is that there's not. Where do you stand on that?

Yes. I think where the question comes into play is when you're trying to correlate it in the context of the bisphosphonates use. And I think what that's telling you is you can't go after this disease chemically. Like it cannot be all about calcium and phosphorous or those together or bisphosphonates by itself. You can't just chemically go after this drug. You really have to hit it biologically and that's what we're doing by taking out sclerostin and allowing the bisphosphonates osteoblasts to lay down more collagen, lay down more bone. That is giving you the degree of bone mineral density, you need to stop fracturing. So for us, in Phase II, it does correlate. In bisphosphonates, I think just when you're going after this chemically, you're not seeing enough increase in bone mineral density to stop fracturing and that's why it's not correlated.

Okay. But you do believe that there is fundamental reason to think that BMD is a surrogate marker for fracture rate?

To me, it has to. I mean, I think if you just look at this physiologically, pathophysiologically, bone mineral density is just that is what is the density and what is really getting at the strength of your bone, and if that's not correlating with your production and fractures, to me, the logic starts to fall apart.

Okay. I mean, based on the ASTEROID study, it does look like the drug is active. So if [indiscernible] Orbit study doesn't work, what would you do in that case?

If Orbit does not hit statistical significant?

Yes. So just to be clear, we've been talking about Orbit this whole time. There's also [indiscernible] study. Let's talk about Orbit.

Yes. And I think -- so it all depends on how close you were and why it didn't work. If you are very close, everything is trending in the direction and the totality of it and looks very solid. It certainly becomes a different conversation with the FDA, with the EMA, with other regulators. I mean to me, once you hit your primary endpoint and everything looks good, yes, it's always about the totality of the evidence, but you have a very high probability of success of achieving regulatory approval. It becomes a different and a harder conversation when you don't hit statistical significance. But there's lots of examples where people have been over -- been able to overcome that, but that's in the context of we were very close, the math failed me somehow, but the totality of the evidence tells you that this drug works. And to me, that's what I always fall back on. It's an antibody. It's taking out sclerostin, we know what it's doing to osteoblast. It makes sense in that Phase II data is very compelling.

So how would the Cosmic study help in that case? So maybe you can talk to us about the differences between the 2 studies.

Yes. And really, Orbit was designed to standalone [ BR ] Phase III trial and it by itself, honestly, it would be a great label. What's great about Cosmic because we know this is coming or we're anticipating this will come, some people will still want to have the debate about the usefulness of bisphosphonates compared to setrusumab. So now for the first time, we'll have a well-designed controlled Phase III trial to have a data-driven discussion debate about the comparison there. So that study is powered for superiority for setrusumab to bisphosphonates. It does go down to 2 years of age, Orbit goes down to 5. So it does go into younger patients, so that's an addition. But to me, it's really the comparison, but direct head-to-head comparison to bisphosphonates.

If you had to just look at the 2 studies, would the likelihood of success of both in your mind to be equal? Or is one a little bit less likely to fail?

Yes. So I think that's an interesting question. It's kind of where you're -- I don't know how you come at this. So if I had to place of that, I would say, Orbit, it is 159 patients that gives you more power. I will tell you, Emil, our CEO, probably would tell you he would place his bet on Cosmic. So I think, obviously, we plan for -- we power them both to be successful. It's kind of where you would lay your bet.

Okay. What if other scenarios happen though? What if Orbit is successful and Cosmic is not?

Yes. So honestly, that becomes a little bit easier. Technically, regulatory-wise, if you have 2 Phase III studies, you need 1 to be positive. So that helps. To me, Orbit again, stand-alone if Orbit is positive, that's a great label. What you would lose by not hitting statistical significance in Cosmic is your ability to defend on your label superior to bisphosphonates. So you would lose that ability, but to me, that's something...

Does that impact some market opportunity?

So again, I think it depends on what the data is telling you. Was it -- 69 patients wasn't enough to hit statistical significance, but you were very, very close. All of the data tells you in total, it is better. You just didn't hit that magic number. If the data is telling you, which I do not expect at all that they're comparable with another different conversation.

Okay. I think the one thing I didn't ask you about is the baseline fracture rate of patients for Orbit. Can you just compare that to what ASTEROID [indiscernible] ?

Yes. So ASTEROID, it's a little bit of apples and oranges because ASTEROID was done in adults. So people do talk about adults having lower annualized fracture rate. I don't think that's because their disease is necessarily changing. I think it's because disease -- because adults understand if I really protect myself, if I really don't leave the house, I can lower my risk of fractures. For Orbit, we obviously included a lot of pediatric patients in both Orbit and Cosmic. The pediatric patients do tend to respond better. But getting back to your question, we really designed entry criteria for patients to come in with an AFR of at least 1.

Okay. Got it. Now the other part of the conversation is about safety and tolerability. Based on what we know so far, is there anything to be looking out for?

No, and that's what's fantastic because it is an infused drug. So you do -- anything off target, you have to worry about what you're not seeing. But we're not seeing infusion reactions. We're not seeing anaphylactoid reaction. So it's -- it appears to date very, very safe, which helps because over time, it's something we should be able to move it to the home.

Okay. The data itself, so would you be showing us both studies results at the same time? Is that the assumption now?

I think we understand that that's what people would like to see. I think we understand if we did, Orbit first and said Cosmic's coming, then everyone would be like what about Cosmic. While we haven't locked our plans in, I think we understand what people's expectations are.

I mean, could it be like a couple of days apart or a few days apart?

It could, but then doesn't just that confuse people.

But I just want to make sure that that's also how you're thinking about it. And then you just remind us what the guidance and timing is.

Yes. So we're saying around end of the year, we're defining a round end of the year as December or January.

Okay. So if it's December or January, both times historically, companies that I've covered have pivoted more towards January. So would there be a reason why you would have to absolutely divulge data, let's say between Christmas and New Year?

Yes. No, we don't. And honestly, year-end is always tricky, and you have the holidays and what are you going to do to the team or not do to the team during that period of time. But I think for us, it's agnostic at the end of the year, we want to give ourselves a little bit of time because, again, this will be in our hands, it will be unblinded. We'll have our statisticians working on this. And then once they're satisfied, top line comes to me. I need to do a sanity check. Maybe I see something interesting and I want, it's another table listing or figure on growth. So then that will take them a little bit of time to generate. And then I'm ready, it goes to Emil. He does his thing. Maybe he wants 1 little thing ran. So if everything is squeaky clean, no one has any questions then it goes fast. If I have a question, Emil has a question, that can add several weeks to the time line. So we give ourselves room to just manage that.

Okay. I think some people were surprised at the length of time it took between -- for the second interim from when that data lock period opens to when the actual data came. Do you think that, that time that was taken to the second interim would be more efficient to this final read?

Yes. I think when you -- honestly, we talked to most people about their metrics are, we tend to go fast. When you're waiting for something and you know last patient out, it does seem to take forever. And honestly, every time a team shows me a time line like this seems like forever. But once last patient comes out and traditionally with a Phase III, you have a big bolus of patients coming in around the same time. So you have your long lead lab like biomarkers like P1NP and stuff that takes a long time to read out. You have to chase on every query and sometimes a query triggers another query. It does take time. This is a big global study. We're covering a lot of territory. So it does all really add up. And then again, once it's all locked in, they have to run the [ TLF ], so we have to go through everything, make it comfortable and get it ready for external release. So unfortunately or for better or worse, but that really does add up in 2 months, not weeks. Going into final analysis, yes, we had cleaned everything up to IA2. That's super helpful, but your labs, sometimes those labs are so long lead times. And given that this is the end of it, we got to make sure we get the messaging right.

And you're going to be doing the same thing, I presume for Cosmic.

Yes, exactly. Yes.

Okay. Got it. So I think we've exhausted the OI questions. So let's move on to what used to be our #1 topic, and I think people have taken a bit of a hiatus from it, which is Angelman syndrome. So GTX-102, can you just remind us about that program, what its mechanism is and where we are in development?

Yes. So Angelman, it's one of those diseases where absolutely no treatment. It's a neurodevelopmental disorder where these children are born and really don't really ever develop. I mean, when we talk about children being on a developmental curve, hitting their developmental milestones over time, these children aren't learning and gaining new skills over time. We talk about developmental curve. Their development line is very flat. The defect is with a gene that produces a protein of the same name, UBE3A. And UBE3A's effect on neurons is how synapses are communicating with each other. What's good about this disease therapeutically is your neurons remain intact. It's not like a lot of neurologic disorders where you're having damage and your neurons are dying. So those neurons are sitting there, not communicating well to each other. And what's also very interesting molecularly is we have a relatively small number of genes that are imprinted. So with Angelman, you really -- we are, neurotypical people are dependent on UBE3A produced from the copy inherited from the mother. The father's copy is imprinted methylated down, is shut down. In children with Angelman don't have a functional maternal copy, they're not producing UBE3A, but the paternal copy is still sitting there in every single neuron. So if you can knock down this imprinting, you can start producing UBE3A in every neuron. It allows these synopsis to start communicating with each other and these children then start to develop on their developmental curve. So that's exactly what we saw in the Phase II. And while not on a normal developmental curve, for the first time, these patients are improving in cognition, improving in speech, learning to walk better, feed themselves, sleep through the night. They really are achieving true developmental milestones that they would not have been able to achieve otherwise.

So there was a bit of a delay in this program kind of advancing to this stage. I think people have discussed this with you about the rate of titration of dosing in the very early portion of the program. I think people are still a little bit confused about ,not confused, but still wondering why the program got slowed because I think Emil had said that it was at the request of the FDA that the company had originally been choosing to titrate pretty quickly to higher doses.

Yes. So we're talking about the original 5 patients. Yes. So this definitely goes back in time, and it really shows you why you don't want to get ahead of yourself with those findings.

And I guess, to cut to the chase, what is the impact to the dose that you've chosen ultimately from what you learned from those?

Yes. So I think what happened is we had to go back really. First, we had to overcome the safety findings with the lower extremity weakness. And that's really what really delayed stuff. It was handling the safety stuff, and we needed to start dose finding from the beginning again. So we had to start very low and work ourselves up again to find what is that safe and efficacious dose. So we took the time to enroll 74 patients in total. And for us, for rare disease, that is a lot of patients. But what that allowed us to do is truly understand what is the right dose because you want enough to knock down that imprinting. But we know ASOs by design, they can be, by the chemical nature, irritating at the site of injection, that is true for all ASOs. So we need to define that right balance, and that's what goes to the heart of dose finding, and that's the regimen that we have brought into the Phase III.

Yes. So you had gone to, I think, considerably higher doses earlier. And so the argument might be is that going to be less potent now that you've gone to a lower dose in order to control that lower? And can you talk about have you eliminated lower extremity weakness altogether?

Yes. So I think sometimes people think like a lot of times in drug development more is better. And that often -- that rarely is the case. So you just -- you want enough to knock down the imprinting, but you don't want to keep just dumping this ASO in there. So you need to find that great balance. And with the number of patients we dosed at the regimen we're taking into Phase III, they are on their developmental curve. They are learning new skills. And we know they aren't plateauing. They're not hitting ceilings. So we'll see how far they can go over time. Again, we talk about gaining developmental skills with neurotypical children, that doesn't happen in days or weeks. It takes months and sometimes a year to gain these new skills. So we are confident that these doses are absolutely effective. And to me, that's clear, we're not working around the edges. For the lower extremity weakness, we saw in all 5 original patients that was much more severe by using flush, which is simply trying to get this ASO away from the injection site as quickly as possible and Trendelenburg, which is just using gravity to help. We're just trying to prevent that irritation outside of injection. A big thing we did, and I think now seeing what's happening in the Phase III could be a very important additional mitigation stuff is we dropped our fourth loading dose. We do think loading, which is dosing 1 month apart before you ultimately move to every 3-month dosing is important to knock down that imprinting because to me, if you need to knock down this imprinting, that's different than maintaining that knockdown. So we want to give originally 4 doses in a row, knock down imprinting and then get to chronic dosing. We dropped that fourth loading dose because we think with 4 1-month doses, if you had a little bit of irritation, you had a buildup in around your fourth dose, some patients were seeing that lower extremity weakness. Once you get to 3-month dosing, there's enough time that if you have a little bit of irritation, it will resolve before your next dose. We are seeing an additional improvement with that mitigation. Can I promise you it's gone forever? I don't know. But I think it is [ very ] to say it has been mitigated. We understand it. It always resolves about sequelae. And again, on the whole, parents are clearly saying benefit risk profile is very positive because the children who did experience this, once it resolved, they wanted to go back on therapy.

Okay. And what is the sort of counterbalance which is -- are you getting enough knockdown by eliminating one of the loading doses?

Yes. So we wanted to make sure, on the whole, it was worth that, that mitigation step for lower extremity weakness was worth losing that fourth loading dose. There's nothing we've done, nothing anyone else has done to tell you, do you need 3, 4, 5, how many loading doses we need. We do think 3 is enough. As a comparison, Ionis isn't using loading doses, so they don't even think it's necessary to do that. So -- but also really depends -- that also -- so that really depends on how you're thinking about this molecular and what -- how this imprinting is working. So that's just a choice.

Okay. You brought up Ionis. I was going to ask about in a minute or 2 later, but let's just talk about it now. Can you -- they're obviously also trying to develop their own therapy pretty much parallel time lines to you. Can you talk about the differences in your molecule and your trial design versus theirs?

Yes. No. I mean, I think they're both ASO, so certainly in the same class here. And I think when you read about the differences, you'll hear about the 3 prime end of the transcript and the 5 prime end where you're targeting, we are confident and there's scientific evidence to support this. Scott Dindot, the one who's published and created this molecule of where we're targeting, we get better knockdown. And to me, the evidence to support that if the doses we're using are much lower compared to what Ionis is using, again, we've been very transparent with the data we have seen. They have released data up to 6 months. I think a lot of people are saying it's roughly comparable. Once we have longer-term data from them, we can see with the head-to-head comparison. So that speaks to dose that speaks to potency that potentially speaks to the importance of knocking down. So the ASOs are different. They target different areas on the anti-transcript. And then Phase III design, we've also taken a little bit of a different path. We have focused on Aspire, all patients with full mutations. Those patients because they have full mutations make no UBE3A. That's roughly 70%, 80% of the total patient population. But importantly, gives you a homogeneous phenotype, which should make signal detection easier. It's neurology, neurology is hard. We are doing the rest of the genotypes in Aurora. So those 2 studies together, both Phase III give us a full label. Ionis took an all-in approach, single study, all genotypes, 200 patients. We plan to enroll at 29. We overenrolled -- 120, we overenrolled to 129. So we made a commitment to patients. So they are looking for more patients. They brought 2 doses into their Phase III as well. To me, the concern with that approach is if you have patients with uniparental disomy, imprinting defects, missense mutation, if you're making some level of UBE3A, those patients can achieve some small developmental gains. Again, I would never call them mild because there is no child with mild Angelman. It may speak to their primary endpoint choice of expressive language because if you're expressing low levels of UBE3A, they may be able to achieve 1 word, maybe 2 words. So that could help them with their primary endpoint. We chose cognition on our 74 patients. Cognition was very strong. It's also, in our mind, a good choice because it is foundational to speech to motor to behavior. So we think all of this is anchored in cognition. The truth is when you look at your primaries and secondaries, together, we're looking at the Bayley across all domains. So at the end of the day, treaters and parents will be able to make a comparison between these 2 ASOs.

Yes. So yours is the Bayley for cognition.

Bayley cognition for primary endpoint. The rest of the domains are secondaries. They're expressive Bayley for the rest of the domain of secondary.

Both you and Ionis had negotiated this with FDA a while back. Is there any concern that what changes that have happened recently, the thinking about having, let's say, a uniform primary endpoints for the same condition. Has that come up in conversation? Or is that a thing to think about when the data sets come in?

Yes. So the FDA absolutely wants to guide everyone in the same direction because they want to be able to make comparisons. So you'll always bring forward what you want to do and they give you advice and whenever they strongly encourage something, they're telling you to. For them, it's really our choice and our risk on primary endpoint because that's kind of how you win or lose, but they will still have that data to make a comparison. We'll have data across all domains. So regardless of what's primary and secondary, they can still do a head-to-head comparison. We're in [ CDER ] here, and I think we've seen some more stability in CDER compared to CBER. So I think that's in our favor with Angelman.

And what is the guidance for when the study is up?

So we announced, again, really impressive 129 patients in 7 months. So that starts the clock. It's roughly 48 weeks, 338 days. So again, with our long lead time labs, cleaning, locking, analysis puts us in the second half of next year.

Okay. And what about Aurora?

So Aurora will bring along in parallel. I don't think that study will not be at full conclusion. So we will do a data cut where we are with Aurora. And we are confident, as long as the safety is comparable, we see efficacy within there, that we'll be able to do a combination of really extrapolation from Aspire, but then also using that Aurora data to really go for a full label.

Okay. Got it. So 2026 is a big year?

Yes. No. I mean, when you look -- basically, you can consider GSDIa and Sanfilippo in filing mode so bringing our approvals next year, OI reads out around the end of the year, Angelman reads out in the second half of the year. So part of the development part of the organization. It's exciting. Hopefully, we'll also be standing at the end of the year, but it will be a big year.

I'll have to squeeze in. In terms of the CRL that the company received, where are you in terms of addressing it?

Yes. So and again, very reassuring with the FDA is they have been very engaged both formally and informally. And with CRLs is they are clear on their expectations for refiling. So I can say we understand what they want for refiling. Importantly, they remain genuinely complementary on the clinical data. So for me, when you get a CRL that says you don't have an adequately design controlled Phase III, you're in real trouble. These types of CMC, these types of findings at the manufacturing facility are relatively easier to do in a shorter period of time. So we're confident we'll be able to provide what they have asked for. And for us, as far as guidance, we're confident we can achieve approval within that window for the [ PRB ] as of September 30 of next year.

Okay. Perfect. With that, we're out of time. So thanks, everybody, for sitting in on the presentation. And thanks again for coming over to see us.

Yes. Thank you.