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

Good morning, and welcome to the Ultragenyx GTX-102 for Angelman Syndrome Phase I/II Interim Data Update Conference Call. [Operator Instructions] As a reminder, this call is being recorded. It is now my pleasure to turn the call over to Joshua Higa, Vice President of Investor Relations.

Thank you. We have issued a press release detailing these results, which you can find on our website at ultragenyx.com. The slides we are presenting today will be available for download in the IR section of our website shortly after the presentation. Joining me today are Emil Kakkis, Chief Executive Officer and President; Eric Crombez, Chief Medical Officer; and Howard Horn, Chief Financial Officer. I'd like to remind everyone that during today's call, we'll be making forward-looking statements. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. Please refer to the risk factors discussed in our latest SEC filings. I'll now turn the call over to Emil.

Thanks, Josh, and good morning, everyone. Glad you could join us for the call. We're excited about the data we have in Angelman Syndrome and to provide an update on this important program. If you move through the forward-looking statement, Slide 3 is just a disclaimer. Of course, GTX-102 is an investigational drug, and we're showing open-label data. And ultimately, we think proof of [indiscernible] safety will require a randomized control studies. Slide 4, so we'll talk today about expansion cohorts A & B data up to day 170 as the main body of the data we'll talk with its new -- is 24 patients worth of data through day 170. We'll also give an update on dose escalation cohorts 4-7 up to date 758, and then we'll talk about regulatory discussions and Phase III planning as well. Let's move on to Slide 5. The GTX-102, as you know, devastating neuroaxonal disorder fairly large rare disease population of around 60,000 commercial successful territories. And we have identified and are developing what we think is the most potent signs behind the ASOs with the targeting of a region near the fire front end, which is, we think, the most potent and the greatest potential in being able to prove Angelman Syndrome. And I think today, we'll show you data to help support that conclusion. On Slide 6, I'll just give you the high-level key takeaways, and then we'll start diving deeper into the study design and the results. Cohorts A & B show rapid and clinical means improvement across multiple domains, and we're very encouraged by what we're seeing. When you look at the improvements, they are consistent or exceeding what we saw before with dose escalation cohorts 4-7 at this -- at the higher doses used in cohorts A & B. Cohort 4 continues to show increase in clinical benefits over time, suggesting that the effect we're seeing on the brains of kids continues to gain ground, the longer we treat. And with this information, we are well set up to start and begin and we have begun the Phase III planning process for this program with our goal to initiate the Phase III before the end of this year. Slide 7 just talks about the domains. These are domains you've seen before at our Analyst Day. What we have basically the Bayley will be showing a day for cognition receptive communication. The ASA is used for behavior, sleep and gross motor. Now gross motor in the past, we've shown Bayley data, but we don't have Bayley at day 170 in the way this was done to help reduce patient burden because the Bayley is a more burdensome assessment, but we will show you the ASA for gross motor for comparison, you can see the improvement in the gross motor. Those are the assessments. And for some of these, we have natural history and we'll show comparisons in natural history where we find them. On Slide 8 is just a little bit more about the natural history data we have. The original data we've shown you before from natural history study 1, which is shown here in older study that included 63 patients, which had the deletion type of Angelman Syndrome in the same age range. So we're only looking at natural history patients that match the ones in our trial. We also have data now from natural history too, which is distinctive in using the Bayley-4 directly. This is a relatively small set to date 365, but will continue to increase as time goes on. But I think if you look at the natural history set, you say that the data is essentially is the same. We don't see a meaningful difference between them. But those will be the comparisons we use where those -- we have data on natural history. Now let's go to Slide 9, [indiscernible] with severe assessment used frequently the ASA score is designed with Angelman in mind. There's very specific 68 questions. they are very responsive to the changes and problems that occur in Angelman syndrome, why these tests are more -- I think, more sensitive and more responsive. And most of the patients are really probably in the 4% to 6% range, somewhere at 3%, but they're mostly in the moderately severe range in their deletion patients. And based on this changing from like markedly to moderately, moderately to mild, a 1 point change here represents a significant change in clinical state for these patients. That's the 1-plus change that we set as a clinically important change for these assessments. Now on Slide 10, we'll just touch on the exposure. We now have 74 patients on drug, what's important. We've been treating these patients for in the cohort 4-7 for 2 for about nearly 2.5 years and the cohort A & B for up to a year. And this combination, the number of patients treated for so long tells you a lot more about safety of the program that you can treat this many patients for that long in dose ranges from 3.3 to 14. We'll be showing you today 24 of the 34 patients that are in cohort A & B. So the majority of those patients in that cohort through date 170. Now let's just talk about who enrolled on Slide 11. So the cohorts A & B, are shown here, both age and sex are very similar and very comparable to what we've showing cohorts 4-7. So the populations really look the same. What's different is that we've enrolled now at 19 sites across 7 countries. We've gone across different language and different settings and are going to show you that we can replicate the same effect across the world, which is a great setup for Phase III. On the bottom of this slide, you can see the dosing regime for cohorts A & B, there's a monthly dose, and then it goes every 3 months for dose 5 and 6 and we marked on here day 170 evaluation in day 224, which are ones that we'll be talking about as we go forward. There are other points of valuation, but not all endpoints are valid every single point because of the burden of doing that many tests. That gives you an idea of how to anchor what we're going to show you in the data that come. So now let's get on to Slide 12. This is where we get into the actual data. Let's start with cognition by Bayley-4 and we're showing rapidly and significant improvement. If you look at the left panel, you can see the blue dot at day 170, we're actually crossing already the clinically and statistically significant change with very consistent tight air bars showing the improvement on par with what we saw before. We replicated now in all these sites. If you look compared to that to natural history on the right, you can see there's barely any movement in the chart showing how much different it is. Now if you look at the cohort 4-7 data, you can see the patients continuing to gain ground across now almost 3 years of time with many fold above the statistical threshold. So this shows that whatever we're doing, we're turning on these brands to continue to work over a long period of time and gain ground, this is very encouraging and I believe that the cognition continues to be in ground with these kids brains start to develop. So the data shows that we are matching what we had before and doing it consistently. Slide 13, we talked about behavior, ASA score for behavior, in this case, you can see the blue line, which is the cohort A & B came down very far, in fact, much further than we did with the ASA in the Cohort 4-7. In fact, doubling the decline rate in that day by day 170. If you look at that line where we hit at 24 patients, it would took us about a year to get there before Cohort 4-7, so we've accelerated that by half, essentially in time. If you look over time, certainly in the cohorts 4-7, they continue to gain ground and get better over time. But the speed and rapidity we're seeing of this effect exceeds what we saw before. On the right, to give you an understanding of what you're seeing in the ASA score, you can see the basis for the 68 questions, excitability, impulsivity, compulsivity. These are all characteristics of abnormal behaviors and you can see the response rate. These are the CGIC scores at day 128. These are whether a patient feels that they -- or the doctor feels that they are better, but plus 1 or better and you can get an idea of what patients are responding to and how they're changing and just gives you comfort in understanding what these ASA scores mean by looking at what we're looking at when we make that assessment. So we're excited about this behavior improvement. It's a very important one for patients as we'll hear about it later. Let's go on to the second measure of behavior. We added another measure, prerogative measure called ABC score, and we're looking at one particular domain within that score, the hyperactivity noncompliance score. And what we're showing you here is the same pattern of response by day 170, a very significant response in this hyperactivity -- reduction hyperactivity, which continues in a few patients that actually made the day 254 as well with a very substantial improvement. And this 1 does have natural history data showing far exceeds out of natural history. So this is just another data with a validated endpoint, showing the same behavioral improvements that we saw with the ASA, giving us comfort in the value and reproducibility of that data. We go on to Slide 15, where the sleep is assessed. Again, the blue dot in the left panel come down all the way to greater than 1 mean. So the mean is already 1 -- a plus 1 score or decline of 1 score already, and that is on par with equal to wherever we got to a Cohort 4-7 already at day 170. So we achieved the level of sleep improvement that exceeds or matches what we saw through the entire day 58 with the Cohort 4-7. Cohort 4-7 have a rapid sleep effect. It is sustained over time. If you look at the anchors, you can see what this represents, night awakening targeted disturbances, the amount of sleep, et cetera. These are different ways that the sleep is improving for patients. But it shows you a broad array of changes that are improving sleep and the fertility gives you comfort that the Cohort A & B dose regimen is giving us a very substantial improvement of sleep, which is a fundamental improvement for patients. On Slide 16, we have the Receptive Communication by Bayley-4. Again, rapid improvement observed on par with what we saw before with the Bayley-4 receptive. And what you can see there in this case is that the AirBars are very tight on that blue dot compared to the red dot. What that tells you is that we're seeing a more consistent pattern of response across patients at this higher dose meaning patients may have been less responsive are moving now, consistent, giving us a more tighter AirBars just gives you a sense that we are having a more consistent pattern of improvement. When you look at the natural history of course, is far exceeds what you see with natural history. And over time, receptive communications continues to gain ground going above the statistical and clinically significant threshold as well. We're encouraged by seeing a replication here of the receptive communication improvements in our A & B cohorts. Slide 17, we'll go on to the gross motor. Now here, we're assessing by the ASA rather than by Bayley because we didn't do the Bayley at day 170. We will have Bayley data later. On the left, you can see that the blue -- the blue line bottom line -- blue dot go well below what we saw in the Cohort 4-7. We're showing a more rapid and more significant improvement in gross motor severity than we saw before, consistent with what we believe is a really important effect on how patients are walking as we've showed you before. If you look across the improvement we're seeing here at day 170 is on par of what we saw maybe with a year of treatment in Cohort 4-7 is showing a more substantial effect at an earlier time point. When you look at the Bayley on the right, which has now some additional data, you can see the patients continue to gain ground by the later time points across statistical threshold. But the Bayley is not really designed for Angelman it's a general test. I think the Angelman severity scale is telling you about the things that affect Angelman, these patients are improving rapidly and give us great confidence in the importance of what we're seeing. That's the main body of data. I want to -- like to go on Slide 18 and just give you kind of overall comparison now, if you look at all the ASA scores and compare Cohort 4-7 with Cohorts A & B. We can see whether you're looking at sleep, behavior, communication or gross motor on the left panel, you can see the sleep has a higher percentage of responders at least a 1 point change or better in every single measure and every single domain. And the communication domain, which is 1 we haven't mentioned before, an ASA just shows the level response, both in receptive and express communication are improved in these patients. We're comfortable then looking at this, the dose we're using is exceeding what we saw before 4-7 Cohort. If you look on the right, we even have with sleep, 10 patients that already have plus 2 improvement in their sleep, which is a profound improvement in sleep and very encouraging. It's very early day 170 time point. So I think what we can show is that at day 170, the new dose regimen is exceeding what we saw before in Cohort 4-7. I think that's very clear and confident about it. If we go on to the next slide, this is the Multi-domain Responder Index, because we didn't have Bayley data, we didn't include the Bayley in this particular version of the Responder Index. We use the other 4 domains that you've seen before. What you can see on the left panel, which is day 170 Cohorts A & B, is that all but 4 patients are -- have a responding domain by day 170, which I think is phenomenal, the consistency of their response. The majority of the patients have 2 to 4 domains already by day 170 and we would expect this to continue to improve over time. You can see a wide variety, different domains in different patients and different combinations, but it gives you a sense for the breadth of across these patients in their response and achieved a p-value with a plus 2 median domain number achieving success and a p-value of course, very small less than 0001. On the right, we show you the comparable, but this is for day 338 for Cohort 4-7, showing you similarly a plus 2 domain median, but with a day 338. So it just shows you that we're achieving the same level of response essentially at half the amount of time in the new Cohort and just shows you how powerful and broad the effect is across individual patients that's easy to see when you're looking at the heat map type approach. Now let's go on to safety and Slide 20. I think the data we've seen show we have an acceptable safety data set and there were no unexpected serious adverse events. So we're very comfortable with what we're seeing with safety. With regard to lower extremity weakness, there's 1 patient from Cohort 7 that we've reported previously that patient has recovered completely. There were 2 new patients that are more recent. They haven't reached day 170 yet. At the time of the data cut. One patient was very mild. It was actually not recognized it resolved within a week and was recognized retrospectively as having it. So it was very mild. One had moderate symptoms, both resolved and are seeing in the study. We're comfortable with what we're seeing here. We think it's a much more minimal effect and very manageable. When we look at what's happened with patients that have had lowering weeks pass, 5 of the original patient with Cohort 3 are all being redosed multiple times without recurrence and having good clinical effect. Cohort 7 patients also has been redosed multiple times now. That's a kid with scoliosis is receiving maintenance therapy now without recurrence. The 2 patients in Cohort B then, there we expect them to continue dosing as they move forward. We've discussed the whole safety profile at our meeting and subsequently with FDA and other regulators notified. There were no issues raised by any regulators, no additional action requests in terms of valuation analysis. I think we're past now this issue being something of great concern. We have to keep our eye on it. But we think it's manageable, and I think the new approach to dose administration Trendelenburg and Flush have resolved this issue and we just need to keep our eye on it. But we think it's not a block of therapy and all patients have been able to get fact free dosed successfully without recurrence. So that's the data, the safety data, now try to get deeper to the clinical meaningfulness. I'm going to hand the call over to Eric Crombez, who will go into some of the physician and caregiver feedback. Eric Go ahead.

Thank you, Emil. Next slide. We also see support for the clinical meaningfulness of the data we just reviewed from feedback from the physicians and patient parents participating in the study. In this slide, you see comprehensive improvements across all 5 domains. And just to highlight a few, you see learning as part of improved cognition. Patients are calmer and better behaved, which helps with school and going out in public. Sleep -- disordered sleep can have an outside impact on not only the patient but also the entire family. We are hearing that improved sleep is one of the most important things to some of these families. Development of language helps with understanding and following directions and we are also seeing signs of development of expressive language. The improved motor skills provide better and safer movement. Next slide. Equally important is the feedback from caregivers. Again, you see how patients are learning new skills, which helps with independents. The improved behavior is providing a level of freedom that they have never had before. The new language skills also improve the quality of the way these patients are interacting with family members. From all of this, I find the most compelling feedback to be from a parent who can now imagine her daughter living with assistance in her own home and contributing something of value. Next slide. We would like to now share a few videos from a patient enrolled in one of the expansion cohorts. While each child is different, the progress that this patient has made within the first 170 days of treatment is remarkable and does generally represent the progress we are seeing in the expansion cohorts. We will start with video taken before enrollment in the trial and then a couple of videos highlighting the development of new skills. Before we start playing the videos, I would like to remind the audience that the video should not be captured or redistributed without express written consent. Operator, please start the video. [Presentation]

This is the before video. This test a puzzle solving evaluates cognition and find in gross motor. Here, you see the patients struggling to hold on to a ball with a pollen and inability to place a ball on the peg. You see that the patient is getting support to stabilize her trunk in a standing position so she can focus on using her arms and hands. When the therapist let's go, the patient leans forward against the table. The only way for her to place the ball on the peg was for the therapists to guide our hand in placement of the ball. Here, you do see the same patient threading beads onto a string as a test of cognition and fine motor function. You can see that she understands the task. She has the ability to independently focus on a task without redirection or handholding and she makes repeated attempts without frustration. This is learning. The pins are grass and finger isolation to pick up the beads are a new scale. This skill is also important for eating with utensils. She is showing evidence of improved cognition by independently focusing on the task without redirection. Angelman patients typically cannot walk down stairs without support. Here, you see that she is focusing on the stairs and exercising caution. This improvement in balance in coordination prevents falls. Reciprocal stepping step over step instead of stopping at each step to put 2 feet down for balance is a new skill. Angelman patients have difficulty walking, especially on uneven surfaces and have frequent falls. Now you see her showing sufficient balance and coordination to navigate uneven surfaces. She is focusing on the task and exercising caution. She is cognitively aware of the branch and risk of falling and actively trying to prevent it. She slows down, thanks and steps over it. To catch the ball, she is showing focus. She is taking direction and repeated attempts or evidence of learning. You also see sufficient trunk stability to focus on her arms which was absent in the first video. The ability to attend to a task, focus and follow instructions is one of the most notable cognitive findings in these videos, progressive increase in balance, coordination and trunk stability to allow for performance of more complex gross motor activities highlight the overall progress that this patient has made within the first 170 days of starting treatment. These patients are generally representative of the progress we are seeing across all cohorts.

Thank you, Eric. I think the video is a pretty compelling in how fundamental changes in life that we're seeing and we see that in a lot of patients. And the feeder we've got has just been tremendous and we're excited about is we think this can do for Angelman patients. We'll go on to Slide 25 and talk about regulatory processing. We've had FDA interaction, including a meeting earlier in the year. We'll talk a little bit about that and where we're going from there. At the meeting, we talked about the study design, randomized placebo controlled trial around size and those elements. And the FDA was aligned with those elements. I think they were pleased that we're taking that direction. And I think it's very important to recognize that with these types of endpoints, it's very important to have a placebo controlled trial to be able to interpret and use this endpoint, not just for regulatory approval, but for reimbursement for these kids in the long run. So doing one randomized trial, I think, is essential to get to where we need to go. With regard to the endpoints, all the endpoints that we need are contained in our study that is the FDA did not ask for any other endpoints, any other measures. So I feel -- feel comfortable that we get the data set we need, and they were happy with that set of endpoints we're measuring. They give us some flexibility with those instruments, but we're confident in what we have is what they're looking for. With regard to MDRI in our discussions, we think we'll probably put the MDRI as a secondary endpoint rather than primary with that discussion, but they are flexible with including it in our data set, which will help support the efficacy of the drug. So feel good about that. We'll actually bring the data we have today back to them kind of come to that final conclusion about endpoints. But we're very comfortable. I think the FDA has been very collaborative in the other authorities equally. So we feel good about being able to get through this without too much difficulty given the data we have, we've shown you today. The safe perspective, there are no issues raised, no additional actions. I think they were very comfortable in fact, we spent very little time talking about it. I think they're well past it as we are. It's a manageable thing, patients return to therapy. And -- it's a reversible thing that's not going to be a problem. So with these data today, probably a little bit more extension data for some of the patients will end up getting the FDA in mid-2024. And -- after that discussion, settlement of the agreement of the design will let you know and our goal would be to get to a Phase III start later in the year. On Slide 26, it's just the Phase III design. It's pretty -- I would say, pretty basic design or randomized controlled trials of 100, 120. The size of the trial is really driven more of having enough safety data and to make sure we're powering all of the endpoints. We don't really need that much, but it's what I think is an appropriate amount for this sizable population. The length of the trial will be decided, but it's likely between 254 and 338. If you look at how the data improves over time, that's the amount of time which we think will get us substantial improvement. With regard to the Phase III patients, we are going to focus on the deletion 4-17 that we've been treating so far. And what we expect is that the other types of patients we include in another trial, not a randomized trial, but an open-label trial to help assure we have the broad label for this indication. But one randomized trial, we think will be enough to prove the efficacy of this treatment. Let's move on to Slide 27. There's been a number of people that asked us to try to give us a sense of power. And what we can tell you is based on -- if you look at the Bayley-4 cognition score, the magnitude of benefit we're seeing to readily support a Phase III, right? At day 338 or day 254 to first 2 rows in the table, you can see the current data compared to the pooled natural history data and you can see the power to do that assessment with 120 patients enrolled 108 completers is well of 99%. That's way overpowered, it does not need to be that great. It just gives you a sense for the level of improvement with the variation, if you take the Cohort A & B data we showed you today at day 170, even there, we're already powered to see that amount of change. We don't think day 170 is long enough, but at least tells you how much more power we have than we require. If you -- in the last case, the 338, if you take the natural history data and thus multiply it by 3, make it threefold higher just as a safety assessment, we still have more than 90% power to detect a change. So the point with this site is say we can readily power and steady to achieve the measuring efficacy of the magnitude and variation that we're seeing in our data today. So we're very confident about that. All right. Good. Let's go on to Slide 28. What we're showing you today are strong and consistent results for GTX-102, positive data from the new cohorts across many sites around the world in 7 countries, rapid and sustained clinical benefit corroborating what we saw before and exceeding in regard to the degree of effect we see by day 170. So we're very comfortable with the trajectory of these improvements and what it looks like going forward. With this strong data and the excellent situation with regard to safety, we're in a position of when we have then initiated Phase III planning, and we'll expect to get to the FDA, get the end of Phase II meeting completed and also speak to other regulators that head toward Phase III initiation by the end of 2024. GTX-102 we think with these data put us in a position of being one of our major products going forward and 1 of 5 approvals we expected in the next 2 to 3 years for Ultragenyx, that puts us in a great position to having a major product that we'll have, I think, a transformed effect in Angelman Syndrome based on data. We still have to get through a Phase III trial, but we are very excited about what we're seeing so far tells us that we have a drug that will do something very important for Angelman patients. That's the data for today, and we are now going to open the call to questions.

[Operator Instructions] Our first questions come from the line of Anupam Rama with JPMorgan.

Congrats on the data. The behavior domain is one that based on prior data, we thought it might take a little bit longer to see a benefit, but it seems like you're seeing better effects than at least we had anticipated. What do you think is contributing to this?

Well, that's interesting. I think it's a combination of things, but of course, improvement in sleep could probably have an impact on behavior as well. I think that there is a lot of their behavior is essentially hyperactive and neurotic and the cognition improvement combined with the sleep probably has combined and give them an effect on behavior. It's very much in line with what you see with the sleep as well. And so I think they're probably somewhat related. When you make patients sleep better, they will improve their behavior. But we're encouraged with the rapidity, particularly at this dose level, what we're seeing.

Our next questions come from the line of Gena Wang with Barclays.

This is Huidong Gena, for the SAE on the 3 patients went from cohort 7 and the other 2 from cohort A & B. May I ask how many doses follow-up? Did they start showing this symptom, how long did they take for them to resolve? And how did they resolved?

Generally, these things happen within around 4 doses around 3, 4 doses around that point. That's where we had seen it, for Cohort 7 within a few weeks, he was better. For the mild patient, it was like are we -- it wasn't even recognized upfront. It was recognized afterward that maybe that they had some weakness and so. For the other one, it was just a few weeks, it's actually relatively short. So these are resolving much faster than we saw in the original is much a milder effect than what we've seen before. So it's within a few weeks and was after some doses, what's interesting is we put them back on treatment and give them multiple doses and they're fine. So it's very important about the technique and how it's being done to make sure that that's being done well, but we feel comfortable if you can read out all those patients and do it safely and show the benefits of the drug. I think we're just confident. It's just one of the things we're going to have to manage, but it's not something that stops therapy with GTX-102.

Okay. Yes, I think since you modified your protocol. So there's nothing like real happened during that like administration. And also, like for higher dose, how many doses have you already doses. Because you mentioned you don't have this symptom right now. And for the higher dose cohorts.

Well, the dosing for Cohort A & B is the higher dose that we're going to be using going forward. So the doses we -- you hear yes, are the dose we're going forward with. So Yes. So we have the exposure in these -- well, it's really like 50 patients, there's 24 today, but we are looking at safety across A through E cohort. So it's more on par with like 50 patients or the patients being treated at this dose level. So the intent of this is relatively rare. And since it's resolvable and reproducible, they really read out, and I don't think that -- I just don't think it's the same problem we thought we'd had. I think the dose administration strategy is allowed us to get better efficacy at a lower dose and reduce the risk of this problem.

Our next questions come from the line of Tazeen Ahmad with Bank of America.

So Emil, can you just clarify what additional data you're waiting for before you go and talk to FDA. Secondly, what preliminary, if any, discussions have you had with the agency on this specific data update? And then lastly, can you provide any feedback from physicians about the profile of the drug as it stands now? I think there might be some confusion about whether or not expectations were to completely eliminate lower extremity weakness since you haven't, how does that impact the overall profile of the drug and doctors views?

Great. So we're not really waiting for more data. What -- because the process of requesting a meeting initiating now. The FDA has not seen this data, this is just data we're releasing, right? At this moment, we just got it ourselves. So well, they haven't seen it yet, but we'll be sending this in, but it takes time to request the meeting, get to the meeting schedule, et cetera in that interval, we may collect some additional extension data that we'll bring to them at the time of the meeting, but we're proceeding to request the meeting at this point in time, and they haven't seen it yet. Regarding the MDRI profile, we have we've not had any issue with doctors in dealing with it, including some of the doctors that had the demand and put people back on drug. I think people are pretty comfortable with it. They understand it's reversible and is certainly much milder than we saw before. So it's certainly a concern, but I haven't had anyone say they don't want to be part of it. In fact, we have mainly doctors trying to call me to get into the study or patient groups repeatedly from various countries trying to get us to bring the Phase III to their country. So at this point, dose changes are not a concern compared to what the benefit people are seeing. So we're comfortable with the safety profile, and we haven't had any feeling of a concern.

Your next questions come from the line of Yaron Werber with TD Cowen.

Nice job in a really tough disease. Maybe I have a couple of questions really, Emil, just on the endpoints. So when it looks at the powering you gave us, talks about Bayley-4 for cognition. Is that your thinking as the primary and then a host of secondaries? Or are you thinking about potentially going something a little bit broader as the primary and then maybe secondly, the 1 data we haven't seen sort of the ASA, the ASA overall or the CGI-I OR the CGI-S, just any thoughts on those as endpoints are you going to sort of dive more into the subdomains.

Yes. So thanks, Yaron. The Bayley-4 cognition is ONE of the ones that has the most broadest importance and impact and it continues to gain ground. So -- we are looking at that as a potential primary. We'll still have that discussion with FDA to verify. But that's one that seems to make the most sense, but we could look at some others. So the idea is if that were primary, then we put some of these other endpoints as secondary with the MDRIs with integrating a per patient basis response to help support the meaningfulness of that. That's our view. Right now the ASA overall -- what I would say to you the domain-specific assessments are a lot more powerful than the overall. The overall basically dilutes out things. It doesn't give you a precise result. We will use the CGIS. We use it here at day 128, so we'll show you that's a change for us, excuse me, the CGI-C's change scores. But the FDA although they allowed that in the Average Phase III, chain scores are not anchored to specific data and are not usually preferred when we're talking about Phase III study. So the Angelman severity assessment, the CGI-S what used to be called CGI-S is anchored by specific questions, so it has more of a fundamental basis. So we'll focus on ASA. We might do CGI change scores just plus 1, plus 2 here and there in the program. But with regard to endpoints, we'll focus on data that is driven off of hard findings on the patient rather than the physician's opinion of how they're doing. So that's the big picture right now, you're on.

Our next question comes from the line of Chris Raymond with Piper Sandler.

Just 2 questions. So I want to understand maybe the plan with younger patients. I know you guys have talked about in the past not wanting to run or not being feasible to run a placebo-controlled trial in younger patients but any sort of plan to address that group of patients and then I know you mentioned Emil, you'd have an end of Phase II meeting here soon. What's the timing of when you'd have certainty around the primary? -- that you could communicate with us.

Yes. So I'll deal with the second question. The end of Phase II is like at midyear. It depends on when net days schedule that we will request it, and then we have to get to that. So it's about mid-year -- and so around that time, we'd expect from that meaning to come to a conclusion on primary endpoint. And if we are fully resolved, we'll put out a notice on where we're at on that interaction. We definitely want to treat younger patients, it's just as a policy matter of policy we don't put little kids in Phase III trials, we haven't stated them before. We do need to understand dosing in the younger patients. But in the long run, treating kids from when they're 1 or 2 years old could very well be substantially better than treating when they're older. So we will want to do that. It will be an open-label format in this situation with the randomized study showing you the cause and effect of the drug. We think in this younger patient study, we can show that in deletion type or other types that the improvement we're seeing we can be confident is a real drug effect. So our expectation is to be able to do an open-label trial. There are also the other genotypes that we want to look at and those could be put together in a basket type trial that we would conduct in parallel with Phase III. We do want to make sure we get the dosing right in much smaller kids, too. So that probably involves some dose titration to get to the right number.

Our next questions come from the line of Yigal Nochomovitz with Citigroup.

I just had a question on the MDRI. I recall at the Analyst event in October last year, the company was positioning that potentially as a primary endpoint for the Phase III and then you mentioned that FDA was more comfortable making that a secondary. Could you just explain in a little more detail on why the FDA was pushing back a bit on MDRI as the primary end point?

Well, we've been talking to MDRI. I have been talking with FDA at various parts of the FDA about MDRI for a while. It's a new approach. It's an individual patient response kind of based approach rather than a continuous variable. I think the FDA expressively said they prefer just a continuous variable primary endpoint type analysis more traditional. I think they're just more comfortable with that. I think the MDRI will be in there and allow us to support the efficacy, and we're comfortable with having it in there as a sort of alternative to looking at cognition examples that were primary cognition involves improvement in a number of different parameters. So it's a little bit of an integrated type of endpoint already receptive communication, expressive attentiveness behavior, all that stuff play into the cognition assessment. So I look at that as being broader to begin with. But MDRI is the key secondary very well, provides the support we need. And I think from my own perspective as a company, we're trying to advance the science of rare disease drug development and putting the MDRI and there will give us a chance in the large randomized study to show how meaningful it is of the approach. Putting a secondary just gives us a chance to get the benefit of it without creating any challenge for the FDA at this point. But we're excited about what we've got because we can make this work at almost any way you can pick practically any endpoint we have and be able to make the study work. So we have a lot of options in front of us. That's not always true. We have multiple endpoints, we could use to get a successful Phase III trial.

Okay. And then regarding the dosing, you've quoted the range many times. Is there a point we're going to be a little more specific regarding exactly which doses within that range were used and how many patients per dose?

Yes, we'll get more specific at some point in time. We're keeping it more secretive now for competitive reasons. But well, we've given you the range. So obviously, the loading goes is within that range. And what I can say from that is that this ASO is very potent, far more potent than those being tested by competitors and that's the key thing that we have the right science technology approach to how you're to turn on the UBE3A gene. And the fact the dose range is so low. I think is what makes us drug special.

Our next question has come from the line of Dae Gon Ha with Stifel.

I guess on the question of endpoint specifically, if we think about the natural history that you presented today, there was a natural history 1 as well as natural history 2 discrepancy there. Natural history 1 seems to be more of a derivative extrapolation versus natural history 2. I know in the powering calculations you kind of assumed 3x just for the sake of powering. But how should we think about the natural history more, I guess, relevant to this case? Is it more natural history 2 or natural history 1? And then I've got a follow-up.

Yes. I think got it actually really doesn't matter. But at Tracy is a smaller set of data, but they're flat for both on cognition. What we're doing in natural history 1 is we ran the Bayley-3. And so Pearson, the company makes the Bayley has a formula to transform Bayley-3 scores into the Bayley-4 scores. It's the same set of questions. So it's really quite it's homologous. The 1 difference is whether there's an extra little tidbit of whether a skill is developing. So they already have a transformation. What we're showing you whether you do it directly or you do it that way, if anything, the direct Bayley look flatter than the NHS 1. So we're comfortable with either way you go. It's not going to change anything, whether you're doing transforming 3 or whether you're doing Bayley-4 directly. By the time we get done with Phase III, we will have a natural history done with Bayley-4 that's more extensive as those patients or 40 patients get through the full year. But I'll say to you in a randomized controlled study won't matter is we're going to be comparing to our own control. But I think what you can see from all of that is whether you do Bayley-3 and transform a Bayley-4 you getting the same results. These kids don't get better on their own.

Okay. And then second question, I understand sort of the lack of clarity on dosing just for competitive reasons. But any more detail you can provide on the safety issue? Like what doses you mentioned sort of 3 to 4 weeks for the Cohorts A & B but what doses were sort of triggering that? And any additional mitigating strategies that you can implement going forward in Phase III.

Cohort A & B, C, D & E are actually all using the same dose. So we set a dose based on what we saw was great efficacy in the dose titration Cohorts. So we came up with a dose based on those Cohorts, and they're all seeing the same dose. It's all the same. There's no distinction between the different patients. And the fact that we see this kind of a little bit here and there randomly and that seems to resolve and you redose suggest it's a little bit more of a procedural thing than it is the actual dose choice. I think the dose choice is a safe dose choice. And we start a little bit lower. They titrate up into maintenance when they go less frequent. The dose goes towards the higher end of the range for the maintenance period, which we've said before that the maintenance period is in the 10 to 14 range. So we're comfortable with the dosing and the dose of save and there's no distinction between having or not having effect. It's just an individual thing and sometimes may relate to a particular site or other technical issues. But right now, we're comfortable that it's resolvable and we get put people back on treatment and doesn't recur.

Our next questions come from the line of Joon Lee with Truist Securities.

Congrats on the data. Did the FDA indicate any desire to coordinate the approval endpoint with, Ionis who may also have data very soon. I mean, if Ionis proposed to a different end point, how with document, which joke to use? And on MDRI, what exactly is the FDA want to see before allowing you guys to use that as an approvable endpoint? I have a very hard time understanding their pushback.

Yes. Actually, FDA has never mentioned Ionis once. I don't -- they've not given any indications as anyone else to coordinate with. I'd look at what we do as a company. We have a whole department that works on endpoints. I think we have a very sophisticated deep team on this kind of work. We've had our meeting with Kyowa and FDA. It was a very good collaborative meeting. I feel like the endpoints are in our decision to make, and I'm not concerned about Ionis at this point. Regarding MDRI. I've been talking to FDA. It was in our Mepsevii program you may remember, we did use it there. We just haven't run it in a big randomized study yet. And I think it's just a new thing, and they're just not sure about it. I think they see the value, and I've had many people inquire about it. But putting it primary ends up for them is they're just conservative and it's okay. We're going to put it in our -- as a key secondary, and that will put us in a position meant get the benefit of it in our program. So I'm not concerned about it. And it's -- as we get it in there and they see how it performs, the truth is, if you want to know how our kids are doing, you look at the MDRI table, and you know how all these kids are doing in 1 visual look across the multiple domains. It's so powerful eventually, we'll get them there. But I've been pushing as an individual in my career, whether here, BioMarin or at every life foundation, we've been pushing the envelope on how to do good drug development. MDRI is one of the things I think that's highly valuable, biomarkers, primary endpoints I've been pushing on as well. The FDA takes time. They have the U.S. health in their hands that I understand they want to be to work quite carefully. We think in the long run, the MDRI approach will become a standard way of approaching these highly variable diseases. And with time the FDA will learn the true value of having an all-comer setting and being able to capture efficacy across multiple domains. And so we just will continue to press ahead on making that change in the long run. But it will be in there, and that allows they are flexible having it in there. So that gives a chance to prove its value, add the shows of what it can do. And I think this will be -- I think Angelman is a perfect disease state for this endpoint given its heterogeneity and broad set of issues and broad set of ages that we're looking at. So we're excited about getting forward with it. But I'm not surprised FDA is conservative, and they should be, they are response where everyone's help and they want to make sure they get it right.

Our next questions come from the line of Kristen Kluska with Cantor Fitzgerald.

Can you talk about your expectation on a placebo performance relative to what we see from natural history and I know the primary isn't finalized yet, but we have seen data from the scale that you're considering for other studies and indications. So do you have a sense of that and how it may impact power and calculations?

Yes. Well, I ran the Bayley, by the way, and a lot of studies in my career, Others like Ali Skrinar, who heads our endpoint development strategy group, we've run it a lot. Open-label, blinded study. It really doesn't move, right? It really is hard to move an Angelman patients don't change. So we feel comfortable that we're not going to see a lot of movements or it's really hard to move the Bayley. This is why we're excited about moving the Bayley because -- she and I both have never seen it happen. And even the FDA was impressed at the Bayley is moving, as it's not a very sensitive test, but to get it to movement, you have to have a lot of effect. So we're comfortable that the assumptions we put forth are right. I threw in as an example, you could triple the size of the natural history benefit and you're still well plenty of power. So I think we have a lot of room here in terms of power being able to demonstrate a difference with placebo in this trial. So we're not concerned at this point.

Okay. And then do you anticipate reporting further updates from these cohorts of patients? And what else more is important to learn from longer-term data at this stage?

Yes, we would expect to report more data. This is an interim look. We'll expect to report when all the patients have gone through and with longer-term data, that could be later in the year. We haven't set exact time line yet for that, but we'd expect to have another by this data where we have all the patients through certain time points. And we're looking forward to that because I think getting more patients through more time will help solidify the confidence we have in program.

Our next questions come from the line of Liisa Bayko with Evercore ISI.

I just wanted to drill down a little bit more on the radiculopathy you're seeing. How is it different from what you saw in those first 5 patients several years ago when you were first testing GTX-102. And how are you more comfortable with what you're seeing at these dose levels versus before when you did have to reduce dose? And then how are you thinking about incorporating that into the kind of trial design if you do have to sort of pause therapy and redose patients, et cetera. How does that factor into your thinking on patient number, et cetera?

Yes. Well, so the In the original 5 patients, they had gotten -- 4 of them got into 36 milligrams and 1 and got into 20mg much higher dosing, and we weren't doing to Trendelenburg flush. At least Genome was not being done reliably. I think what we're seeing here is much milder, much more rapid. There it took a few months for some patients to resolve fully. Many within weeks to months. But here, we're talking about weeks, it's much shorter. The degree of impairment is much less. So it's a lot more transit. In fact, 1 of the patients that wasn't even recognized they had a problem until in retrospect, it was gotten back and realized. So what we're seeing is something much milder and not as significant as it was before. It's still important, but it's nothing like what it was before. With regard to Phase III, we're looking at the incidence of this as being relatively minor. And so it's less than 50%. So we don't think it's going to have a fundamental impact on the Phase III, but we are looking at that in our design. We assumed 10% drop out. But keep in mind, if a patient has an AE in a study, they're still going to be counted in the study, right? But a lot of the data those patients when they get back on drugs, still have improvement in clinical benefits. So I don't think they're going to detract from the data significantly. But we are paying attention to it in our design. And we come out with that later in the year, hopefully, that will help explain our approach to managing that.

Okay. That's really helpful. And then just 1 additional question. Just historically, if you were looking at the natural history, how well has that tracked with what's been seen in randomized placebo-controlled trials? Has it been pretty predictive or to give us some context for any examples of that, that would be helpful.

Right. Well, a lot of people look at the randomized controlled placebo, where they had a CGI Global Impression Scale score that had a 0.7% change in the placebo group. But that's a physician opinion change, right? This endpoint is a psychologist evaluating very specific questions in the kid. It's a very different thing. It's not based on opinions based on what the kid does. This is why I think it's a lot more rigorous and harder to move. And therefore, I think you'll have a lot less background change. It's very hard for kids to do something they've never done before and can't do randomly. So it's just the rigor of a psychologist come out the PI very specific set of questions. It means the natural history, I think, will be more consistent with what you see in the trial. And that we wouldn't expect to see a lot of placebo or bias going on. Now the design of the trial is also not going to be 12 weeks or very short, which was what happened before. The trial will likely be 250 to 338, which is well past the period of what you normally think of placebo effect or bias being optimal or maximal. So I think those are factors that will help mitigate that kind of impact on the trial design. And given the max amount of power we have, I just don't think there's going to be an issue even if you had more signal than you thought in the natural history or in the control group.

Our next questions come from the line of Joseph Schwartz with Leerink Partners.

I have a question on safety and then 1 on efficacy. For safety, I'm just wondering if you could talk a little bit more about the drug administration technique and how important you think this is for avoiding SAE now and how consistent has this been across study sites? And what will you be doing in Phase III?

Sure for safety, the drug administration method, basically the patients are done. The TAP is done, drug is pushed in and Flush and then the patient is put in Trendelenburg within a few minutes. The technique is standardized across all these sites. The fact that we have now dozen sites across 7 countries and now with the U.S. to 8 countries, being able to do it. I think it's not hard to do. And most of the sites we're using in this Phase III trial are actually being essentially prep to be Phase III sites. So that should give us some consistency just with what we're doing now and what we expect to see, right? So a lot of these sites will become the Phase III sites as well. So that helped us essentially train them, get them optimized technique. It is not an unusual thing, by the way, due from Trendelenburg or Flush. So I think we've not seen a problem in applying that consistently.

Okay. And then on efficacy, how much will the overall efficacy assessments change between Phase I and II and Phase III? Are there any additional levels of blinding or any other considerations that we should keep in mind with how efficacy is going to be evaluated in the next trial?

No, it will be essentially the same in terms of the endpoints. I mean whether we change any endpoint at all, I think it would be very minimal, if any, but we have the flexibility to do so. But we're going to be running these endpoints the way we run them. And so we wouldn't expect any other levels of control. It's just a traditional randomized 2 group comparison. So it's pretty time to now in terms of design and execution. And as they have as a company based on our own internal policies and approvals we always run in Phase III the same way we run things in Phase II in terms of the endpoint, how it's conducted and what we do to avoid any changes which might induce a new variable. So this is part of our policy how we run Phase III in rare.

Our next questions come from the line of Maury Raycroft with Jefferies.

Kind of a follow-up to some of the others. But just wondering if there's anything else that you need ahead of the end of Phase II meeting and what exactly do you need to align on the endpoint for the pivotal with FDA? And then separately, what are gating factors to redose the 2 patients in cohorts A & B?

Sure. So we'll probably include a little bit of longer-term data when we finally get the FDA. But the data package we have now over the main data package, a few patients getting through day 254 or 338 will probably include it at that time as closer to the time of we get there. But there's nothing we're really waiting for. We'll be able to get that short-term -- I mean, longer-term data at the time we go to the meeting. Now in terms of getting settled on the endpoint, we think we have all the information that we need. There was really no fundamental problem with what we're doing from the agency in terms of what we're assessing, how we're approaching it. So we feel we just need to go out and propose, here's what we're going to do and here is why and show them how the power works and what the efficacy looks like when we get there. So I don't really expect there to be difficulty in coming to that conclusion based on the discussions we've had so far -- the other question was on I'm sorry, what was your second question?

Redosing the 2 patients in Cohorts A & B, One of the gating factors for redosing?

Yes. The gating factors, generally, we're waiting -- we'll wait to see if there's any protein elevation for the protein, what happens is the drug can have some local inflammatory effect. We see some protein elevation. So we wait for that to resolve and then they get redosed.

Our next questions come from the line of Salveen Richter with Goldman Sachs.

Two for me here. One is on time lines. Just an understanding here whether the trial would start by year-end? And alongside enrollment, should we assume about 2 years until data and then with regard to ex U.S. regulators, is there any synchronization with regard to what you're discussing with the FDA as well?

Yes. So the time line would be to get the Phase III started. We've designed the Phase II, as you can see with many more sites than we really needed and the purpose was to get them set up to be Phase III sites to treat a few couple of patients get the method set up. That -- the hope of that is to be able to activate those sites more quickly for Phase III than before as part of our learning in the post-pandemic world by setting them up, having contracts, understanding methodology that will be better set and trained essentially for Phase III. So a lot of the cycle the majority of the sites are Phase II, there may be a few extra. That will help get the sites up and enroll quicker. I don't think it's 2 years from data. I don't want to set a timeline precisely today. But our goal will be, if this drug is working, we'll want to get it enrolled this prompt list. It sites up and enrolled as promptly as possible and complete the study and clean a lock as promptly as we can. So I don't want to set a time line yet for that. But it is important to move this along. It's such so valuable for patients and for us to get this done promptly.

Our next questions come from the line of Jeffrey Hung with Morgan Stanley.

This is Michael Riad on for Jeff Hung. Has there been anything to suggest age-dependent differences and clinical benefit, specifically between Cohorts A versus B or C versus D, just trying to figure out, based on the disease progression, is there an optimal age for preventing skills from getting lost versus helping to regain them.

Well, I think it's a really important question. When we first started, I think a lot of people felt that the older kids wouldn't respond, what we've been surprised with they actually do respond. And I would say to you, I can't tell you a distinctive difference in response that we have patients responding across the age range. And that's encouraging because I think people thought the older kids couldn't respond, but they actually do in very important ways. So right now, that's why we're including that whole age range. We started wide thinking if we had to -- some didn't respond, we narrow it down. But in fact, up to 14% are responding. And the question becomes what about adults and someone asked earlier about what about younger -- younger for sure, but I think you have to look at some adults. I think if you made kids calmer, slept better more functional cognitive, that's going to affect someone at any age. What I would say to you is that the theories about human development based on mice have not translated well. And the fact is that human brains are more plastic more evolved to be able to adapt and change than what any mouse model. And so the mouse model. So the mouse model they would suggest that after a certain age the benefit would be minimal. It's not really turning out to be true. And I think that's a great thing for Angelman patients. It means we probably could do more. I think there's no doubt treating early would have a better developmental outcome. I think that seems very unlikely. But right now, we're not seeing a distinctive difference, which is why we haven't shown you A versus B, right? We're including A and B together because there's really not a distinct difference between the groups.

That's helpful. And then based on that, there wouldn't be any sort of age preference for recruitment for the Phase III?

It's going to be the same age range, and we'll probably include -- we'll probably stratify the ages to make their equal between the 2 groups that there's not like a shift of all young in 1 group and all old in the other group, certainly, but there's not a great deal of concern about you'd like to see an even spread of age across the 2 groups.

Our next questions come from the line of Whitney Ijem with Canaccord Genuity.

Just a quick 1 for me. Have you looked at the EEG data from this data cut? And is it consistent or anything of note there relative to previous updates?

Yes. We didn't present EEG data because the EEG in this part of the EXPAND study was more focus that have U.S. sites. It was just not done in all the sites. And so there was -- there's isn't much EEG debt at all from the ex U.S. side. So as we get the U.S. sites reporting data on the other cohorts, then we'll have more EEG data.

Our next questions come from the line of Ed Arce with H.C. Wainwright.

Great. Thanks, Emil, for taking our questions, and congrats on the data. Just 1 question for me. I'm focusing on the cognition as the likely primary endpoint here in -- given the administrative strategies used in the more recent expansion cohorts versus the others where a lot of these domains actually improved. I'm wondering if you can give some thoughts around why cognition with the Bayley-4 was consistent but didn't really improve versus the prior cohorts. And would you expect these strategies to yield some improvements over longer term?

Yes. It looks like the Bayley -- the Bayley is the more difficult to move instrument. It's just more rigorous, more constrained. It doesn't match Angelman severity, Angelman disease state very well. So we see it operating the same, but the negative effect is still large enough for us to use it as a primary. The ASA certainly is responding more quickly because it's really hone -- but if you go long enough cognition is getting to where it needs to be, and we feel comfortable that, that will be true. It may be that for cognition because it's complex and a lot of features to it that it takes more time to improve -- to readily improve. You can see the curve continues to gain ground over months, right, over even a couple of years. So we think that's what you're looking at. You're looking at a complex neurological process moving along where if you look at a specific thing like sleeping or behavior, those changes are very specific narrower and you can detect the change quicker, but the integration of them into a cognitive outcome may take more time. But we're not concerned about it. The fact it replicated using multiple countries and a broader number of sites tells you that the data is solid. It's not like 1 site or another site or a country having an effect and others not. So we feel good about cognition being a reproducible and highly recognized endpoint.

Great. And then perhaps just 1 follow-up. Given the effects, the correlated effects of sleep on behavior, I'm wondering if you've had any specific discussions around that endpoint with the FDA and how you think about it in the overall design for Phase III?

Well, we've talked about all of those endpoints. Behavior certainly is very well respected. There's been other drugs approved on behavioral type endpoints. So that's certainly something the FDA has seen. Sleep is an area of more complexity for the agency, the sleep endpoints, I think in this case, when we talked about it, we were talking not about subtle changes of sleep, but profound changes in sleep. And FDA, if you're talking about these profound big changes, they appreciate how that's important because it's an effect on caregiver and everyone else. So the ASA score is really looking at profound changes in sleep not subtle. It's not like 10% more deep sleep or something settled. It's really I'm not sleeping at night and now I'm sleeping through the night, right? It's that fundamental. And I think that kind of sleep change the FDA is comfortable with. It's not planned to be a primary -- but we do think it's an important secondary and it's important because it responds very quickly, profoundly and probably is part of contributing to the improvement in brain function that you see through other endpoints as too as well.

Our next questions come from the line of Jack Allen with Baird.

Congratulations on the data. My questions are somewhat in the same line as the most recent questions asked, but I was wondering if you could dive a little bit more into the sleep data and the effects seen there. It seemed to level off with a longer-term follow-up from the Cohorts 4-7. I guess how are you thinking about the impacts on sleep and the long-term ability to continue to improve sleep?

Yes. Well, the truth is once you start sleeping well. It's kind of hard to keep sleeping more well, right? So we have kids now sleeping through the night, then they've gotten better. And so then it's a little bit harder to distinguish a difference. So this is what -- they're getting a rapid response, kids sleeping to the night and that's -- that's staying there. So that's why it's probably -- I think it's not getting , but I wouldn't necessarily expect to be better. But what's most important, if you look -- as the patients would have really poor sleep have the biggest response to sleep. And we get to patients who have mild or minimal sleep problems. I think once you're there, there's not much more you can get. Does that make sense? You kind of -- it's like a floor effect, you can't get much better and sleep in a certain level of improvement. So we're not concerned about that. I think in fact to sustained is important over a long period of time. I think the data we're showing now to Cohort A & B the new dose and the dose and the regimen shows a more reaching as good as they get for the entire couple of years in the Cohort 4-7 we're achieving in day 170. So we feel good that this rapid effect is showing the drugs effect and we'd expect it to be sustained and flat. Actually, we're not necessarily expecting fleet to continue to improve over time. It should get very good and stay good. That would be our expectation.

Our final questions will come from the line of Yaron Werber with TD Cowen.

Just maybe the follow-up. Just Emil, on the deletion. So it looks like you're going to be looking at the same [ 1513 ] deletion Class I, II and III. Can you give us a sense of what percentage of patients does that include? And can you get a broad label? Like the label going to say children essentially with Angelman and what's the strategy for adults as well?

Yes. So thank you, Yaron. Our strategy on labeling is to anchor the data set with the 4-17 represents the majority of the Angelman patients out there. That will be the placebo-controlled proof of cause and effect for the drug. We'll then still in the labeling with open-label arm studies, this is something we've done in the past with multiple programs, right? So this is the way you can do it. You don't need randomized studies in young or in adults or another situation. We think we can do this if we have 1 high-quality randomized study in the most severe population. So our expectation is to do a basket say where we look at young patients, we will look at patients with the missense and the UPD type as well. And we should include another arm of that study, which would have adults as well. And the idea we to show safety in all these populations and to provide support of the efficacy data, which we think from my history in working rare disease would be enough to get the full label, and that's our approach we expect to take.

And you can run them in parallel or are they sequential?

Yes. We would run in parallel. We'll get the Phase III up and running and then start the basket trial with a separate team. So they can run. And we might put the basket trial at sites other than where the Phase III is to not cause interference. There's a lot of people, a lot of patients with missense, UPD other types that are pinging us frequently. Because they want to get in on the story. But we decided to keep Phase III narrow. As our habit is part of our referrals is you don't study in Phase III people. You have the studies in Phase II. And so we don't want to broaden the genotypes and create noise in the system in the middle of a randomized call Phase III. Since we're studying the severe patients in Phase III, we think that is a rigorous test of the drug, right? It could be with missense patients that might have a better effect because they're, let's say, closer to the edge of being normal, right? They have some activity, not none. So in EPD, there's 2 chromosomes that turn on, so that could be also a benefit. But we'll study those and we'll be running that in parallel. We'll start the Phase III first is for 4 probably set up a separate team to work on the basket, include some other countries in the basket trial as well. to allow -- to get broader international exposure, and there's a lot of interest internationally getting part of that program.

Thank you. We have reached the end of our question-and-answer session. I would now like to turn the floor back over to Joshua Higa for closing remarks.

Thank you. This concludes today's call. The slides from our presentation have been posted to our website. If you have further questions, please reach out to us via e-mail at [email protected]. Thanks.

Thank you. This does conclude today's teleconference. We appreciate your participation. You may disconnect at this time. Enjoy the rest of your day.