Ladies and gentlemen, thank you for standing by, and welcome to the Ultragenyx GTX-102 for Angelman Syndrome Interim Data and Program Update Conference Call. At this time, all participants are in a listen-only mode. At the end of the prepared remarks, you will have an opportunity to ask questions during the Q&A portion of the call. It is now my pleasure to turn today's call over to Joshua Higa, Executive Director and Head of Investor Relations. You may begin. Thank you. We issued a press release and posted slides that detail this interim data and program update, which you can find on our website at ir.ultragenyx.com. Joining me on this call from the company are Emil Kakkis, Chief Executive Officer and President, Camille L. Bedrosian, Chief Medical Officer, Scott Stromatt, Chief Medical Officer, Neurology, Mardi Dier, Chief Financial Officer, and Thomas Kassberg, Chief Business Officer. I'm also pleased to be joined on this call by two investigators on our study, Dr. Erick Sell, Associate Professor of Neurology at Children's Hospital of Eastern Ontario in Ottawa, Canada, and Dr. Elizabeth Berry-Kravis, Professor of Pediatrics at Rush University Medical Center in Chicago, Illinois. I'd like to remind everyone that today's call will 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. Thank you, Josh, and good afternoon, everyone. We're here to talk today about the GTX-102 mid-year interim update and program update. There's a slideshow that we'll be referencing during this call. On the second slide is our legal warning, which Josh has just provided. On the third slide is a disclaimer that GTX-102 is an investigational product without proven efficacy and safety by FDA or any other authority, and these are interim data updates for an open-label study and specific limitations of that design. Ultimate proof of safety and efficacy will depend on the conduct of an adequate randomized controlled study. Move on to slide four are the groups that are here today. I won't go over that again, but we have a great team of people to help answer your questions later in the call. On to slide five. What we're showing to you today in our release and the slide deck is that we're seeing promising clinical data for GTX-102. We haven't seen clinically significant safety issues, AEs or SAEs that relate to the drug up to 10 mg using the new administration strategy. No lower extremity weakness and no pattern of increasing inflammation, which is extremely important. In addition, at these lower doses, we are seeing clinical activity in multiple domains on multiple measures, and most subjects with three or more improved domains. We're comfortable that we're seeing strong changes in results in these patients that are drug-specific, and we're encouraged by what we see so far. With the data we saw early on, we proceeded to actually initiate a Cohort six and seven, which would start at the new higher doses that we have shown are not causing any inflammation, the 7.5 mg and 10 mg doses. We've already cleared that with U.K. and Canadian authorities, and in fact have dosed the first patient in Cohort seven. We're moving ahead already with loading doses starting at these higher levels, which we expect would achieve higher accumulation and improved, further improved efficacy. Finally, with the strong data we have so far, we have triggered the GeneTx acquisition, and we'll talk more about that in a little bit. Let's dive in to the story. On slide six is a summary of the protocols. I won't spend too much time, only to kind of remind you there's a Cohort four, which is young patients, a Cohort five, which is older patients above age eight. That in the Canadian, U.K. protocol, we're doing a dose titration for all the patients at two different ladders, and there is a Trendelenburg and flush opponent component of how the administration is being done. In the U.S., it's only the younger patients are at the 2 mg dose and maintained without dose titration. On the next slide seven is the general outline for dosing, and this is important for you to kinda gain understanding of where the doses are and where the evaluations that we're gonna be talking about. There's a baseline evaluation after which dose one is given. During the monthly loading phase, there are four doses in general will be planned at monthly intervals. Before the dose three is given on day 58, we will check for what the clinical changes are seen and if they're sufficient to keep the dose or escalate the dose. At day 128, after the fourth dose, we do a major assessment evaluation, which is the major body of the data we're presenting today. Some patients have progressed to the PMD or maintenance dose evaluation at day 170. Between day 120 and 170, there's no more drug given. It's just more time of exposure to the existing loaded drug. Subsequently, they will be getting every three-month dosing. The furthest patient in the trial has reached actually the second PMD dose, but all patients have gotten through the four doses at this stage. That's sort of the dosing schematic. We'll be referencing those times as we go through the deck. On slide eight is the summary of the dose exposure information. I don't wanna go through all of this with you, but just to highlight a few of the key points. In terms of cumulative dose, we have patients going up to 32.4 mg, and 7 of 14 patients have 20 mg or more, which was the level at which the lowest level at which a safety event was seen before. In addition, we have patients now have gotten up to six doses without. And some of those exposures, 13 of them are greater than 147 days at which we had previously seen a safety event. Eight patients have now more than six months of exposure. If you look at the maximum dose exposed through the titration, we have now patients getting 10 mg and 7.5 mg of dosing at their most recent doses without the adverse effect. We're pretty comfortable now that both in dose and exposure, we're showing that this drug at this doses and with this administration strategy can be done in a reasonable safety. Now safety details shown on slide nine. In slide nine, we show there's no drug-related SAEs and no AEs or SAE reports of lower extremity weakness. There have been some unrelated SAEs, which are of no significant consequence, and the most common AEs you can see there are in a minority of the population. Therefore, we're very comfortable with what we're seeing regarding the safety experience, so far acceptable. Importantly, when we look at CSF total proteins, you can see the graph at the bottom of this page. We're seeing very stable CSF protein, no trend of improvement, no signs of the inflammation that would result in increased CSF protein, which might indicate a problem that was observed last time. There is one patient that did have an asymptomatic infection leading to a rise in CSF protein, which was transient and resolved, but unrelated to the drug. We're comfortable so far with the safety profile and the lack of inflammation as measured by CSF protein. Now let's go into slide 10, which is the efficacy. In the upper panel is the Cohort Four, and in the bottom panel, Cohort Five. Seven of nine patients show improvement in at least three domains. We're seeing multi-domain improvements across many patients. What is very notable, of course, the sleep has a very strong effect with four out of six patients showing a significant effect there. But many of these patients have multiple domains, and we're seeing effects and improvements across many domains in the study. In Cohort five, similarly, multiple domains are improving, and this is giving us the same kind of pattern we saw before in terms of a variable multiple domain response across these patients. Now, in the next slide 11, we're introducing you to an Angelman Severity Score. The first score, the change score was a relative score. The severity score is an objective score. It looks at criteria of a series of items that will determine where you are on the score. So it's just more of an absolute score and more rigorous. When you look at the same set of data in Cohort 4 and Cohort 5 using the objective severity score data, we see a very similar pattern with very strong sleep results and multi-domain improvements across the range in Cohort 4 as well as in Cohort 5. We're seeing the objective criteria showing us a very similar pattern, what we saw with the relative change Angelman Change Score. Now, if you look further over time, this is day 128. On the next slide 12, you follow the patients that have made it to the PMD visit. There are four patients, three from Cohort four and one from Cohort five. What's very striking here is that there's one patient you can see from Cohort four that's now achieving multiple domains. It's of two-point or three-point improvement effect. Every domain is improved at least two or three points on the objective scale, and it's a seven-point scale, so these are meaningful changes. These improvements are greater than we've seen in this trial at day 128, which suggests that once there's patients loaded, that they can continue to improve over time. We think this is very encouraging to see that kind of broad effect across multiple domains in this patient, who's actually the four-year-old, who's the youngest patient in the study, which I think is very enlightening with regard to the drug and what it can do. Now in the next, we're gonna go through and deep dive into some of the particular domains and give you some commentary, both from the objective scale as well as from caregivers. A deep dive in the sleep domain I think was important. We saw a number of patients with significant improvements in the sleep score. These are severity score changes. Three of the patients were two, three, or four-point improvements. I think you can see from the scale down at the bottom, the kind of things, these are not all the items, these are just two of the seven items that are being scored in terms of creating a score. To go from a score of six to two, as in patient 001 did, that is a change from severely impaired to slightly impaired. If you look at the caregiver's commentary, you can see the support for what a profound improvement in sleep is observing for some of these patients that were, for example, not able to sleep and waking up multiple times and now sleeping through the night or having much fewer awakenings. We think this result is very similar to what we saw before. In this study, we have actually more patients with sleep problems, but it's very similar to what we saw, particularly in patient five in the prior study, with a very substantial sleep improvement. On slide 14, we'll dive into the behavior, the Vineland score. Most patients have improved in this score, and this is the personal self-care subdomain, not the whole of the Vineland. This is how they take care of themselves, feeding, eating, toileting. The two patients achieved statistically significant results in the Vineland score. Most of the patients did improve. You can see some of the verbatims on the side, which tell you a little about how patients are changing. They're using a fork, opening doors, et cetera. We think it's still early for the complex type of behaviors involved in the Vineland, but we're encouraged to see the improvement going forward so far. On slide 15 are some comments from patients around general behavior, that is adaptability, interactions with others. I think what we're seeing here is very similar to what we've seen before in terms of patients being calmer, being more responsive, more interactive. We're pleased to see these kind of changes happening, which are important for families in their daily lives. On slide 16, we'll dive into the communication domain. The Bayley score, expressive and receptive communication, improved in most patients. In three patients, there was statistically significant improvement in receptive and in expressive in two patients. One patient under the receptive in Cohort one had an inexplicable drop, even though that patient had a very strong ORCA score, and we believe that was just a bad day at test. Subsequently, at the PMD visit day 170, that patient showed statistically significant positive response in receptive, along with the other two patients. All three that reached day 170 had statistically significant improvement in the Bayley-4, and they also showed trends of improvement in the expressive communication. We're encouraged by what we're seeing here with communication on the Bayley-4. Now, if you go on the next slide, the ORCA, which is the caregiver evaluation, is a complement to what you see with the psychologist-administered Bayley test. In this score, we see the ORCA in that one patient achieved 14.2 statistically significant and another at 5.7, and several patients with positive scores. The verbatim here suggests what patients are seeing from a standpoint of communication. Being able to use their device and string words together to make a sentence is certainly important. Some of them trying to make sounds is very similar to what we saw before in terms of patients beginning to make consonant noises, which preceded their transition to actually saying words. So far, we're encouraged on the communication domain. On slide 18, the next one, we touch on fine motor and gross motor. We've seen gross motor improvements, both Cohort four and five, and good improvements as well in the fine motor in the Cohort five. In the Cohort four, some variation in response in Cohort four. We're encouraged with the type of things we're seeing both in fine motor and gross motor, particularly in walking, which I think is really important, both because patients with Angelman, especially as they get older, can have very great difficulties walking, and you can see those improvements, but also because it tells you that these patients', lower extremities are in fact improving, which just further helps confirm the fact that we're not seeing a safety issue with the lower extremity. On slide 19 is the EEG data. This data was more mixed. It was not as distinctive and not as strong as what's seen in the previous data. We believe we probably need to have a higher loading dose, and we'll continue to watch EEG going forward. On slide 20, Cohorts four and five are entering the therapeutic range with acceptable safety. When we look at what we're seeing, we're not seeing any drug-related SAEs, [inaudible], stable CSF proteins. This tells us that given the oligo, the ASO at this dose, and with this administration strategy, we can avoid any inflammation that might be a cause of a safety event. We see encouraging clinical activity both in the change score and the severity score, but it's supported by a number of different secondary evaluations, which help show that these changes can be clinically meaningful, for some of the patients. We think that's very important, especially with multiple domains positive in most patients. It's also important to know when you look at the three Cohort four patients that reach PMD, that in one of those patients you see a substantial progression in benefit beyond what was seen at day 128, indicating that they've been loaded with sufficient amount of drug to achieve the knockdown, we believe, which is enabling them to show continued progress over time, suggesting just more time might help these patients do better. When you look at the details of what we're seeing from the patient verbatims and the results of these tests, it's clear the pattern response is the same. The type of changes we're seeing are very similar to what we saw before. We feel now with a whole different seven batch cohorts in different countries and different patients, we're getting very much the same pattern. With doses now at 7.5 mg-10 mg already cleared, not showing this effect, starting the next phase at those dose levels, I think we're pretty confident that we should be able to achieve a higher load effect than we would expect to see even further enhanced, efficacy. That's the story with the data for now, and I'd like to introduce Scott Stromatt, who has joined Ultragenyx. Welcome, Scott. Scott will be interviewing our guest, investigator guest today. Thanks, Emil. It's a pleasure to be here. I'd like to introduce our audience to Dr. Erick Sell. He's one of our leading investigators in the U.K. and Canada. He's enrolled the most patients. He's an associate professor of pediatric neurology. He's at the Children's Hospital of Eastern Ontario in Ottawa. Erick, thank you for being on the call with us today. From your experience and your perspective, would you tell us your view on the safety and efficacy that you're seeing so far in your patients? Thank you, Scott. Yeah. We're seeing encouraging results early in terms of. Clinical activity across the different domains. Without a hesitance, I find that these are related to the medication. On a very positive note, we haven't seen any drug-related safety issues. I personally feel that the therapeutic effects could be enhanced as we have started to go a bit higher on the monthly loading doses and as we continue to increase in the maintenance part of the protocol. I can see that in general I do see evidence for a therapeutic effect of the study medication, and I haven't seen any side effects related to the medication. Thank you, Erick. Another question. Can you comment on the dosing administration strategy? We administer the drug by LP, then there's a flush, and then they're placed in Trendelenburg position. Can you tell us about how that is tolerated by the patient and the families? Yes. In our center, it has been very smooth. We have a sedation done by a colleague anesthesiologist. It's a light sedation, usually with a combination of sevoflurane gas, plus minus propofol, depending on the criteria of the anesthesiologist. With that in place, it's very easy to do the lumbar puncture and inject the study medication at the moment that we're placing the patient in Trendelenburg positioning and give the 10 mL flush. We then take the patient to a recovery area with the other patients that are recovering from anesthesia. We haven't had really any issues that were unexpected. Often the patient is gonna wake up just before the time of Trendelenburg, and the nursing staff at the bedside will count them. We call the parents, and in that way, we complete the 45 minutes of Trendelenburg positioning. Then the patients quickly are recovering or followed in the clinic for the rest of the protocol. Other than one instance where a patient had nausea and vomiting, which was related more to the anesthetic process because the patient had had anesthetics in the past and had that common issue of nausea. Everything has been very smooth. Okay. Thank you, Erick. That helps gives us some color and perspective. I appreciate that. I'll turn it back over to Emil to move on to the U.S. slide. Thanks, Scott and Erick. I wanna just touch briefly on Slide 22 on the U.S. clinical data. I won't go through all of it in detail, but it's the program that we agreed on with the FDA. On Slide 22 are some paneled information using both the change score as well as the varied scale and the Bayley in receptive express communication, fine motor, and gross motor, as well as the ORCA. We think the data are showing, again, support even at 2 mg dosing, and for these two patients loaded. These are younger patients only, I'd remind everyone. The safety, I think, was very similar to what we've seen before, so we're very comfortable with that. We're encouraged by it by the data so far. I'll invite Scott then to talk with Dr. Elizabeth Berry-Kravis, who's been with this program for quite a while. Thank you, Emil. Good afternoon, audience. Dr. Elizabeth Berry-Kravis is a professor at Department of Pediatrics and has enrolled the most patients, has had the most experience with GTX-102. Liz, given the totality of the data that you've seen and you were presented today, how does this compare with what you've seen in the original five patients? I would say, Scott, the response to GTX-102 does vary some between patients and is definitely something that builds with time. In short times, we don't get the whole story. I would say that the early responses that have been seen in the recent patients treated with the lower doses are quite similar to the kinds of things we saw in the first five patients on the higher doses early on. There's small changes when you look at the whole spectrum of development, but they're quite exciting when you work with kids with developmental disorders who just don't learn new things quickly, and when you look at the speed of acquisition of new skills and the rate of development in Angelman syndrome. The data from these new patients, I would say, mimics the first five patients in that there are changes across domains, and there's a confluence of data on multiple measures showing that all the measures are moving toward improvement in the patients. There seems to be more rapid change in those who are younger, but there's still variability even within a certain age group, as we would expect with any drug and any disorder. Thank you, Liz. When reading the verbatims from the patients and the parents, excuse me, just the parents, what the patients are doing in terms of communication, sleep, gross motor, and other areas, what is your impression compared to natural history? You touched on this earlier. What is your impression compared to natural history? Could you go into that a little bit more? Yeah. I think these patients are actually describing very similar things to what we heard from the first five patients, things like using a fork better or sleeping through the night. They are describing early changes that are clinically meaningful to families. These changes are in fact being identified not just by the families, but there's early movement on the performance-based measure, the Bayley, and the clinician interviews of Vineland, and some have even had significant improvement on the gross scores in particular areas. Some have had improvements in areas that aren't even detected on any of the standardized measures, things like swimming. The kinds of significant improvement on gross scores on these tests take years to show change in natural history of Angelman syndrome. These are—this appears to definitely be a different rate of progress than what we've seen in natural history. My experience is that the changes have been surprising to me as a person who followed Angelman patients for a long time. It's the amount of change that we saw in a few months, both with the early patients and with some of the later patients, is certainly more than I've seen in 20 years of trials in neurodevelopmental disabilities because it's proven very difficult to treat the underlying core symptoms in these disorders. I would say the early evidence suggests that when this drug is used, that even at the current doses, it's changing the rate or pace of development. Because rates and paces produce improvements over long, long times, it definitely suggests we need to study the drug over an extended timeframe to see how much change is possible. It's very encouraging. Thank you, Liz. Thank you, Scott. Thank you, Liz and Dr. Sell. I think they'll be here for questions in the post period. I think Dr. Berry-Kravis is very right. The fact that there is variability, the patients are all very different. The fact that we see multiple domains in each patient with its own pattern, I think is very encouraging. With what we've seen already and what we've known regarding the protocol in Cohort four and five, we did file and get approval movement forward both in Canada and U.K. on treating a new cohort at a higher dose level. Our expectation is to treat two patients in each cohort. This is at 7.5 mg starting dose for the young patients, 10 mg starting dose for the older kids. They can titrate further one more step, similar to what we were doing in Cohort four and five, but starting at 7.5 mg and 10 mg. Getting closer to that 10 mg dose level that we felt was the level at which we got consistent knockdown in non-human primates. The screening had began, and first patient, in fact, Cohort seven, has already been dosed, and so we're off. Now we are hoping to redose some of the original five U.S. patients in Canada, and that should start soon. We want to get those patients treated again. They're very interested in getting treated and getting started again. Now, opening the protocol in the U.S. will depend on submitting and review of the interim CSR that the FDA has requested from us. That process will be getting going because it is our plan to get their acceptance and begin to open U.S. sites. In the meantime, we continue running in the ex-U.S. setting. Now, our next program update, sometime late 2022, early 2023. I think we've given you a very substantive update today. Now, in 2025, we made the decision to acquire GeneTx and complete early that acquisition and take control of the program. This is because we're confident in the value of the program for Angelman syndrome. We are convinced what we're seeing in both the H and FD evaluations is early stage. We're comfortable on the dose range we achieved so far, and that we're very close to the dose range that we think will be optimal. Therefore, we're confident in our ability to get there given the safety we've seen so far. We think Dr. Dindot and the foundational work funded by FAST, patented on the intellectual property of the gene region and the understanding of the molecular biology, I think is very critical and very unique and valuable to us. In addition, we've learned a lot about Angelman syndrome biology, and the fact that Angelman syndrome can reverse, that these symptoms can change, and we're seeing that again replicated with different investigators in different parts of the world. I think that's an amazing opportunity when the biology works. We can't fix the biology, but if the biology can reverse and improve neurologic function, that's an important element of our decision. The combination of our data, the IP, and the biology put us in position to drive forward a development program. By taking on the program ourselves now we're able to impart more effort into the control and the execution of the plan and head toward phase III planning as we continue to collect more data. We are excited about what we're seeing so far. Now, the deal terms shown, we had negotiated with GeneTx for an earlier option of $75 million upfront, which now has a $30 million milestone for phase III first patient high. There are other details. Ultimately, there are regulatory and commercial milestones and tiered royalties. It is exclusive rights to global data and in support of GTX-102. It does include, in fact, additional alternate ASOs that are in hand. Final slide, on slide 26. We are all in on Angelman syndrome. I can't imagine a more powerful place to be where the biology has given us and the molecular science, the insight into how to change a disease that I thought as a medical geneticist couldn't be changed. We're actually gonna be able to change the outcome for this disease, and I can't imagine anything more powerful and important for us to do as a company, develop the first-ever treatment for Angelman syndrome. We need to continue to optimize the therapeutic benefit, managing the dose administration to get to where we need, but we think we're close, and we're encouraged by what we're seeing so far. Given the scientific basis and the biology, as we've just discussed, we have to do that early dosing, and we're enrolling now, and we're forming alliances with GeneTx team. That basically is a great story of families, five of their children investing in science, finding an opportunity and turning it into a therapeutic. I wanna give my tip of the hat to Paul Evans, Allyson Berent, and Scott Stromatt for, and of course, Scott Dindot, who did the original science, to put this together in the matter of a few years and put forth an opportunity to change the future for Angelman syndrome. Our intent is to be the, develop the first approved therapy for Angelman syndrome. That's it for the presentation, and we are ready for call. Operator, give the instructions for the call. Thank you. Ladies and gentlemen, to ask the question, you will need to press star then one on your telephone. We ask that you limit yourself to one question and one follow-up. Again, that's star one to ask the question. Please stand by while we compile the Q&A roster. Our first question comes from the line of Tazeen Ahmad with Bank of America. Your line is open. Hi, guys. Good afternoon, and thanks for taking my questions. You know, just to follow up on the dosing that you've done so far versus what you want to do, you know, it looks like you've dosed up to 10 mgs individually, which I think leading up to this update, you had hypothesized could end up being the best dose. You know, if you were seeing that clinical activity that you mentioned, why do you want to dose higher to 14 mg? Then secondly, on the acquisition, was there anything in the terms which required you to acquire the company at a certain point in time? I guess, would you have to have paid more if you chose to make the acquisition later? I might have a follow-up. Thanks. Very good. Thanks, Tazeen. On the dosing, keep in mind we've reached the 10 mg dose, but that's in during the maintenance phase. What we're really doing is starting at 7.5 mg and 10 mg during the monthly loading phase, which should achieve a higher load. We don't necessarily say we're going to 14 mg. It could go higher, but we think simply by taking the dose levels we've achieved and giving them now monthly will allow us to get to where we think we need to go. It could be that we're at the dose, or it could be for one or both parts, they need to go even a little bit higher. We're right there, and I think the key thing difference is that we achieved one dose, but now we need to load over a period of four doses to achieve the level of drug we think will give us our efficacy. Now on the deal acquisition, there was an original deal, and then we made an amendment. I'll ask Tom, if you would like to just briefly touch on the rules of the acquisition. Sure. Thanks, Emil. In April 2022, we entered into an amendment of the purchase agreement, which did provide an earlier option based on interim data to acquire the company. As you noted, there are differences. In fact, on the early option, there is a lower upfront. It's $75 million upfront versus $125 million originally set out in the purchase agreement. That would've occurred towards the end of this year. By exercising early, we will have made a $75 million payment or thereabout to GeneTx, the shareholders of GeneTx. There is an additional $30 million milestone that will be due upon the initiation of the phase III, so first patient in that phase III study. A total of $105 million versus the $125 million that originally was described as the upfront in the purchase agreement. Net savings of $20 million- Right. -presuming those- The original deal, that did put time limit for execution. Correct. Yes. It would've happened later this year. The question is, do we wanna do it now, or do you wanna wait till later year? Our view was better to go now, we had enough data to give us confidence and accept a little bit more risk, but with a discount in the upfront price. That was the deal, Tazeen. I see. Okay. Operator, next question, please. Thank you. Please stand by for our next question. One moment. Our next question comes from the line of Joon Lee with Truist. Your line is open. Hi. Thanks for the updates and for taking our questions. Can you elaborate a bit on the numerically superior CGI-I-AS improvement in the U.S. cohort versus the Canadian and the U.K. cohorts that got much higher doses? Is that a function of how CGI is assessed in the U.S. versus Canadian and U.K. cohorts or something else? What did you see in the comparator arm in the U.S. cohort? Related to that, you know, assuming your next trial is going to be a registration trial after seeing Cohort seven and six and seven, how did the data today help you with the powering assumptions and the size of the subsequent trial? Thank you so much. Yeah. I think when all the investigators evaluating the CGI will be doing it on the basis of their insight and knowledge. I think when I look at the overall data, and you look at all the supportive objective data, I think what you'll see is that the ex-U.S. patients with the higher dose have stronger data in terms of the numbers of the other objective criteria compared to the U.S. patients. I think the data are consistent in that way, and I wouldn't overread the CGI change for interpretation at this point. With regard to powering, it's a little premature to talk about powering. What I'll say to you is that there is. I don't think there should be a problem in designing a study that has this many domain improvements to work with. Normally, we're dealing with one thing and other things. Now there's variability, but we are the kings of variability management. That's what we do at Ultragenyx. Everything we do is about variability. In fact, I give talks about variability. That's something we'll be good at, and I have no doubt that we'll come up with a great power in combination with Scott, Camille, and [inaudible] team. We'll figure that one out. We have a lot to work with right now. We need to get the dosing, understand, quantify efficacy, and then work out with the authorities what's a way to capture the multiple domains of impact of a treatment in a complex disease like Angelman. That's a discussion I'm gonna be very excited to have. Great. Can you comment on the, what you saw in the comparator arm in the U.S., cohort? Yeah, we don't have any comparator arm data at this point in time, so it's not there yet. Honestly, it was something FDA has to do and we are gonna do, but we don't have any data yet to report. That program's a little bit further behind the others. Thank you. Thank you. Please stand by for our next question. Operator, looks like Dae Gon's having a hard time connecting. Why don't we move to the next question? All righty. One moment. Our next question comes from the line of Gena Wang with Barclays. Your line is open. Thank you for taking my questions. I have two questions. Thank you for sharing all the data. Since you share all different endpoints, I have a first question is for the both doctors. What in your view could be approvable endpoint, and what magnitude of change that could be considered as clinical meaningful? One question for the company, for Emil: What magnitude of improvement would you be looking for at the higher dose cohorts to expand to the maintenance dose? Hi, Gina. I actually would not put that question to the doctors at this point 'cause it's really a speculation of what would be an approvable endpoint. I don't think it's worth having a speculation right now. There's a lot of things to work with. You're asking. Yeah, second question you asked was on the higher, what we expect from higher doses. We would expect to see more patients have improvements in the multiple domains in the communication area as well as in fine motor. We think we're seeing improvements. We think it could be better based on what we've seen before. We'd like to see some of those domains to improve further. We also are gonna gain more experience with time. That is, the patients that are loaded now will have more time, which we'll also gain just watching them and seeing are they on a trajectory of gain? That is, the patients as they currently loaded on maintenance, do they keep gaining ground as one patient did? If they do, that gives us more indicator about the time and process for improvement. We'll learn about dose and how rapid some objective things, and we'll learn a little more about time as well and how much time we might need to get to an optimal efficacy point. Is four months enough? Is six months enough? Maybe it needs to be eight months. Somewhere in there, we'll gain the ground that will help us understand the best choices. Thank you. Thank you. Please stand by for our next question. Our next question comes from the line of Cory Kasimov with JP Morgan. Your line is open. Hey, good afternoon, guys. Thanks for taking my question. Emil, I guess based on this update, how are you thinking about the potential timing of a phase III registration study? I guess related to that, how much do you first need to see from these additional cohorts with the higher loading doses? Thank you. Yeah. Well, obviously, it depends a little on whether we get to the mark of efficacy we wanna see before we decide. We're doing the next cohort. I think we're very close. Is that the cohort, or do we have to do one more? This year will be spent testing those patients getting. If we hit our mark in this dose or the next step, you know, we would expect to be collecting data this year into early next. Our expectation, though, is to be able to talk to FDA once we have enough patient data to kind of say what the efficacy looks like and how we might design the study. We'd hope to be able to get to that later in the year or early next, and our expectation would be to head to phase III in 2023. We haven't really yet specified exact timing for that, but that would be our target. Okay. In terms of your discussions with the FDA and this upcoming submission of the interim CSR, is it your expectation that this would lead to better alignment between the FDA and international regulators in terms of protocol? Yes, our goal is to gain alignment that the U.S. and ex-U.S. protocols are doing the same thing. We just need to give the FDA convincing support for, one, that we can dose lower this drug and using this administration strategy and do it in a safe and effective way. That the issues that they have raised before or questions they've had are answered sufficiently that they no longer are concerned about other aspects of the mechanism. We think we have that information. They just would like a formal report in this division, and that's what we'll provide them. We would expect them to get there and would be deriving and seeking their agreement on synchronizing the global protocol to move forward so that when we head into expansion of a cohort, once we hit it, we'll be using that both U.S. and ex-U.S. sites. Okay. Makes sense. Thank you. Thank you. Please stand by for our next question. Our next question comes from the line of Joe Schwartz with SVB Securities. Your line is open. Hi. Thanks very much. I was wondering if you've done any analyses to understand whether the loading dose or cumulative dose are more important drivers of efficacy. It seems like the efficacy seems to increase over time, and I'm wondering how much of this is due to an increase in dose throughout the trial versus some other factors like accumulating effect, for lack of a better term. Yeah. -here. Yeah. You know, we sort of do that experiment in patients in humans that we've done so far, right? It's hard to gain that insight. We have gained the insight in the non-human primate studies that were conducted. In those non-human primate studies, we show that you could get to the knockdown with a single dose at a high enough level, or you could get there with separate doses. One dose of 3 mg can get you knocked down, but also three doses of 1 mg can get you to the knockdown, spread over a few weeks. It's pretty clear that the drug has a long half-life and that you can accumulate using small doses that are given frequently. I think in this situation, there's a combination of two things. You have to have enough drug, but you also, in the end, have to have enough accumulation in the brain, and that's what we think we can get to. Now that we're hitting the 7.5 mg and 10 mg dose range, we think that loading at that dose range will get us closer to what we think would be the level that would result in consistent knockdown of the antisense transcript based on our non-human primate data. That's why we think we're pretty close. So far, I would say the non-human primate data with what has been pretty accurate at what we're seeing. We feel pretty comfortable that it is predictive. Very good. Thank you, Joe. Thank you. Uh- Please stand by for our next question. Our next question comes from the line of Yaron Werber with TD Cowen. Your line is open. Great. Thanks for taking the question. Emil, I have a couple related questions. I mean, I guess the first one, from hearing you, it sounds like you're still trying to figure out whether it's gonna be a CGI AS primary or a multi-domain sort of responder score. Is that correct? And do you need to validate an MDR, or can you do it based on the emerging data from this study? And then for secondary endpoints, I imagine you're not contemplating doing like a full Bayley or a full Vineland, but rather some of the subdomains. And will FDA or MAA require those to be validated ahead of time? Thank you. Well, I can guarantee you that they will require whatever we're trying to prove for efficacy and get labeled, they'll want validation. That's why we have Dr. Ali Skrinar and an entire team of people that spend time designing and validating our endpoints. The CGI Angelman syndrome, either the change score, is one way of going. The problem with the change score is it generally is a relative scale and therefore not intrinsically objective or meeting guidelines necessarily proving clinical meaningfulness in and of itself. The Angelman severity scores have criteria in terms of the scoring, and so it actually provides a little more confidence of what is meaningful or not. We are willing to go whichever way the regulators want us to go. Our feeling is, if you want our clinical insight choice, is that we should be using a multi-domain type endpoint because a multi-domain type endpoint will capture the totality of the data, and we capture a variable population of patients and get the most out of them. Within the MDRI, remember that we don't have to validate the MDRI exactly. Within the MDRI are actual endpoints like the Bayley Receptive Expressive Communication. That would be one domain that we would include. The MDRI is basically includes a series of validated domains, but we have to pick a minimally important difference that we'll score off of, and we have to provide support for that score. The MDRI is really, I would think of it as an analytical tool rather than exactly an endpoint of itself. We believe with the validation of some of the instruments we're talking about that with support for the appropriate MID that we can get that. Now, this is a novel thing. The FDA has generally not been so accepting of new things, but we are a company that pushes things ahead that are new, including we use the MDRI in our MEPSEVII approval. It was in there as our key clinical secondary endpoint, and it was positive. We also used a novel trial design in that program, and we've done a lot on developing other types of endpoints, including the RGI-C scoring system for XLH, which didn't exist before. Let me tell you, Yaron, we're good at that. We will figure that out, and we'll validate whatever we have to use. Our hope would be to use something that covers multiple domains to get the most out of the efficacy and to achieve the most in terms of labeling. If it doesn't work that way, we end up with a change score as a primary. I'm comfortable with that also, that we can hit that, and that we'll use then secondary endpoints, individual domain endpoints to help fill out the labeling of the product. Operator, next question. One moment for our next question. Our next question comes from the line of Dae Gon Ha with Stifel. Your line is open. Hey, good evening. Thanks for taking our call and questions as well. Congrats on the progress. I guess one question or one follow-up. Can we go back to slide 16 and 17, Emil? You briefly discussed it, but just kinda curious on how the Day 128 data affected Bayley-4 to a different extent as ORCA. Just trying to get a sense for those two metrics given it's administered by two different, I guess, technicians or professionals. Secondly, we've also heard through talking to KOL that there seems to be work being done trying to establish an MCID using the Bayley scale and could be published sometime next year. I guess how thinking about the trial plans for Cohort six and seven, I guess how would that kind of factor into your overall endpoint decision, if any? Thanks so much. Okay. Thank you. On slide 16, 17, just to be clear, the Bayley is conducted while the patient's in the room with the psychologist, and it requires them to perform. They have to actually perform, whereas the ORCA score, which is on the next page, is the parent communicating, filling out, essentially responding what they're seeing at home. That could have been during the last, you know, period of time rather than today alone. Does that make sense? Remember that ORCA is testing the family is testing the patient in their normal personal environment at home, whereas the psychologists are in the clinic that day. Did something happen on the way in? They didn't get the breakfast they want, something else happened. All kinds of things can happen to make that happen, and it's just part of the nature of these type of instruments. They're noisier 'cause little things can cause problems. When we look at the big breadth of the data, the patients are getting better. This patient had one low, but obviously turned statistically significant positive just six weeks later and had an ORCA score that was well beyond the threshold of statistical significance. We think that shows that the patient really is improving, and we're encouraged by what we see there. Now regarding Cohort six and seven, look, the Bayley and a number of these instruments have a lot of normative data. They have a lot of historical use, and there's a lot of data to help support an MCID or the new terminology we appeal to just MID. That's the minimally important difference. We think it's not that hard for those type of scores. There's a lot of use and a lot of data to help establish what is the minimally important difference. These statistically significant marks that you see on the presentation are already based on thresholds that would be considered clinically meaningful. The big statistically significant in this threshold would mean clinically meaningful. We feel like it's achieving that is very possible here, but we need to achieve it for the majority, if not all the patients, not just some of the patients, right? That's where decreasing the dose, we hope to gain knockdown of a similar level across all patients so we see those kind of changes across the board. Thank you. Operator, next question. Thank you. One moment for our next question. Our next question comes from the line of Yigal Nochomovitz with Citi. Your line is open. Hi, this is Carly on for Yigal Nochomovitz. Thanks so much for taking our question. Can you comment at all on what you observed at the day 58 assessment? I guess just curious if some of the changes you saw on CGI had been observed by day 58 or if they didn't surface until After the patients had been escalated to the second dose level. Sorry if I missed this earlier, but what's the expected timing, if you have it, for adapting the protocol in the U.S. to more closely match the ex-U.S. dosing? Thank you. Sure. Day 58 we saw something similar. We were seeing improvements, and we actually talked about that on our Q1 call, at least the first few. We saw something similar, but as we noted then, the patients still titrated, so they didn't achieve the 2 + 2 [mg] that day 58. In general, they titrated. We began seeing the improvements really within the first couple doses, but we wanted to keep titrating until we saw a trajectory improvement that felt more consistent with achieving optimal knockdown. For the U.S. protocol, we have to do the work to prepare the CSR, the submissions to the agency. That will take a little bit of time, and our hope would be to get that started here in the second half so that we can contribute. It would be hard to predict the FDA and their response in this area. I do think we have answered all the questions, and I think we have substantial data on the protocol going forward. We hope to be able to get that to them and get that going later this year for the U.S. patients. Great. Thanks very much. Thank you. Our next question, please stand by for it. Our next question comes from the line of Maury Raycroft with Jefferies. Your line is open. Hi. Thanks for taking my question. It seems like for patient 003, who's four years old, showed the most benefit on CGI. Can you talk more about specific observations you're seeing based on age, kinetics of efficacy in the younger patients, and then what you expect to see going forward in the younger versus older patients? Yeah. It's a pattern we've seen before that seems like the younger patients may respond more quickly and potentially at lower doses. What I would suggest to you is we created two groups in our dose ranges, 4-8 and 8-17. What I would say is those are very crude dose groupings. The fact that the very smallest, youngest patient had a strong response, just like patient five last time had a very strong response at 20, it tells you that when the patients are small, the effect of the drug may be higher, concentration may be achieved, may be higher. It just indicates to us a little bit more about the dose response. When we see the young patient having a better load and effect, it just tells us we're very close. We're entering the dose range, and for a smaller patient, that dose is already sufficient to get them where they need to go, whereas perhaps in a larger patient, we need to get to a different dose. This age and dose response, ultimately with this, and hopefully when we expand to 20 patients per group, will give us better insight in the right dosing algorithm to optimize for a small patient versus an old patient. Now, aside from the dose, the loading effect, there's no doubt that younger patients likely respond faster from a biological standpoint than older patients, and that's been seen even in the animal model. The truth is, what's encouraging is we're seeing nice effects across the age range. Even the 13-year-old in this study, the oldest one, actually showed some nice effects. We definitely will have to incorporate both the time of effect and the relative dosing to come up with the best regimen or dosing algorithm for the drug. Right now, that information has helped us see that maybe we're entering the range and we're close. Thank you. Operator, next question. Thank you. Please stand by for our next question. Our next question comes from the line of Salveen Richter with Goldman Sachs. Your line is open. Hi. Thanks for taking our question. This is Tommy on for Salveen. We wanted to first ask about the patients who are not improving on the domain. Do you know what could be a driver behind that? Maybe it's the low loading doses, duration of follow-up, or just the patient heterogeneity. On safety, could you just provide some more detail on the COVID cases and the upper respiratory tract infections? Like, how serious were these, and did they happen around the same time? Thank you. Thanks. I'll comment on the non-improving, and I'll let Scott comment on the COVID and the other cases. With regard to improving, first of all, even in non-human primates at a dose level, when you're below the optimal, there was definitely variation between animals. When you're below the dose level, there's probably subtle difference in how much drug is distributing and getting to where it needs to go, and to what degree the biological effect occurs. It's not that surprising that there's some variation, especially when you may be not at a dose that's saturating, in a sense. We don't see any, let's say, obvious reason why some patients didn't respond. They're in the middle of the range of the others. They're not a particular age or a type or character that we can see. It's still a bit random, but I feel comfortable that if we move in the dose range, it will be more saturating. We should get a more consistent response across patients. I would say no matter what, with a disease this variable, there will always be some variation in response. No one will be the same. Honestly, it's been like that with every rare disease treatment we've ever done. Now let Scott talk about the COVID cases and URI, and I'm very happy that that's what we're actually talking about from safety, because everything else was good. Yeah, exactly. We had four cases of COVID, happened at varying points of the trial. Not surprising. I think any investigators will tell you that these children are always putting things in their mouth, and so they will be exposed. The upper respiratory infection was a common cold. The same thing, four cases at varying points in the trial. They were all grade one. All assessed as not related, obviously. The emesis, you didn't ask about that, but that also occurred sporadically. Didn't occur with every dose, probably related to procedure. One of the children has a stress response. When they get stressed, they vomit. But it didn't happen with every dose. Thank you. Thank you. A moment for our next question. Our next question comes from the line of Liisa Bayko with Evercore. Your line is open. Hi there. Thanks for taking the question. I apologize for the background noise. They're doing, like, massive construction in the office beside here. Thank you for sharing all this data. It's a lot to digest here, so I'm sure we'll have more questions as the time goes on. Just a couple from me right now. The Bayley-4, you know, you mentioned Emil seems to have more variability than, say, ORCA. I was wondering about the CGI scores. You know, maybe the doctors can comment on, like, how many of these things are a moment in time, and how might that look from one day to another? Like, how much is above and beyond what might be like background noise or either sort of developmental milestones that may be achieved? Could you just comment on that? Sure. Well, I think the thing you have to expect about the Bayley is we're dealing with, and I think Liz has talked about this variability issue, which is these are severely impaired children, and now you put them in an unusual setting with a person they don't really know, a psychologist who's gonna test them. Their reaction to that situation may vary on that day. I think even without any change, there will be that variation. With change, there may be another part on top of it. The CGI has one benefit is that in this case, it's the doctor and doctor they may have seen multiple times and may be more comfortable with, who's doing their evaluation of the patient and having various inputs. I don't know if, Scott, there's anything you think that would help distinguish the two between them. Do you want Liz to address that? If she wants to talk about the CGI, certainly, Liz. She's worked on the instrument and works first line patients and these patients. Liz, you wanna make a few comments? Like the reliability of CGI maybe. Okay, I can go ahead. I think we worked hard to anchor the CGI so it would have specific kinds of items that would define how problematic the person's symptoms of Angelman are in different domains. When we're doing the CGI, we're asking about the symptoms over the past week or over the past two weeks, depending on how it's defined in a particular study. It's not dependent on how that patient performs in the moment in clinic. Of course, we do take that into effect also. The CGI is a global composite of everything the family tells us the patient is doing, the videos they may have sent us, what the teacher says they're doing in school, and what we see in the patient when we see them in clinic. As a result, it's not so dependent on performance at that moment of time as the Bayley is. Thank you. Does that mean that it's a little bit less variable, you would say, than like the background variability is less? I'm just trying to distinguish like signal from noise kind of factor. Yeah. The goal of the CGI is always to not be too variable. That's why in many studies, we anchor the CGI so that this rating means this and that rating means that. We do fidelity training with the clinicians that are in the study, particularly for registration studies. It is, yes, supposed to be less variable when you work hard to get alignment between the clinicians on what the different ratings mean. Can I just ask one more? Just on the same concept of CGI, the severity versus like the C rating. So how do those really relate to each other? Because it doesn't always track. You have a change that may be zero or minus two, but then it sort of shows up slightly differently on the sort of minimally versus much improved or no change. How do those kind of relate to one another? Well, the severity score actually has objective items with specific score for the Angelman syndrome that we've set. That severity score is a summation of those items that comes up with the point score system. It is an objective scale. It's not a relative scale. That means it's assessing today what these things are you're seeing. But when you look at the other score, the CGI is an interpretation of how they were at baseline versus how they are today, right? And setting a criterion for what's minimal, what's moderate, what's very much. I think that becomes a little bit more subjective. There are criteria that you anchor on, as Liz has put forth, but you're still trying to compare two things, and so that involves some level of judgment when you're making those comparisons. With regard to the FDA, they have accepted the change type four. That's what Ovid had in their phase III. Historically, change scores have been less accepted because they have the issue of recall bias, and there's a tendency to prefer instruments that are assessed objectively and in a timely manner. I think the fact that it is accepted is good. I mean, it's a sensitive tool, but the objective criteria are actually harder and more rigorous because you have to hit multiple things in order to make it work. I'd look at severity as being objective and more rigorous and to some extent, a better way to determine clinical meaningfulness. I think the relative scale is sensitive to showing that something's happening in the trial that's meaningful. The quantification of it is a little bit different. I don't know if you want to add anything to that, Scott? No, I think you covered it. The change is looking back to baseline from day 128, and severity, you're looking at that point in time and what the values are and then. This is a question. Yeah. Good. Hopefully, that helps, Liisa. Thank you very much. Yeah. Thank you. One moment for our next question. Our next question comes from the line of Joel Beatty with Baird. Your line is open. Hi. Thanks for taking the questions. First, for the comparator arm data requested by FDA, how far behind is that, and is that something that would be in the next update in the late 2022 to early 2023 timeframe? Then also for vomiting and emesis, how severe and how long lasting was that? I'll offer this. Scott go ahead. Yeah. In terms of the vomiting and nausea, we had one patient actually swallowed an EKG lead, and that caused vomiting. Probably had some preexisting viral gastroenteritis. This was one of Dr. Sell's patients, and the patient was hospitalized for a while to get the vomiting under control. This is a patient that responds to stress with vomiting. She's had multiple injections. Sometimes she vomits, sometimes she doesn't. The other episodes of emesis are grade one. So again, they don't occur every time. They're fairly sporadic and mild. What was the other- Comparator arm timing. Yeah, the comparator patients have all completed the day 128. The FDA wanted us to look at these instruments from baseline to day 128. Those have all been completed. Those patients are now being dosed at the 2 mg here in the U.S. Now that they've completed, we'll collect that data and do that analysis and present that at a later time. We didn't have the date one. Day 128 we didn't make in time for the. No. Yeah. They weren't available at the time we did the data cut. Right. They're in progress. As I said, they already passed day 128. We just have it by the data cut-off for you. Got it. Thank you. Thank you. One moment for our next question. Our next question comes from the line of Debjit with Guggenheim Partners. Your line is open. Hi, this is Ry Forseth on for Debjit. You mentioned earlier that the viral infection could be attributed to the oral behavior of the patients. Is it possible that also the steroid regimen is playing a role in the viral infection? Our second question is, you've mentioned the dose projection kind of based off of safety and efficacy. Does CSF PK/PD play into your dose projection at all? Have you determined an ASO half-life? First of all, the patients are not getting steroids in the protocol, so that's not really related to the viral infection or not. I think COVID was rampant in the U.K. and Canada, so that's kinda what it was. In fact, I'm happy it was only a minority, not the majority of the patients that got COVID because they're going back and forth to the hospital. We don't think that's related to anything from the protocol or a difference. On the dose, we believe the CSF volume probably is a factor in the PK/PD of the drug. That is, the amount of drug, the concentration of the drug in the CSF is what the brain gets exposed to. It's one of the reasons why we're thinking that the dose might need to be higher in older patients versus younger patients, and that's partly why we stratified the two dose cohorts for starting dose. I think CSF concentration is a factor, and we'll, we're gonna be paying attention to that when we come up with defining a dosing algorithm for different ages in this program. Thanks for that. Thank you. One moment for our next question. Our next question comes from the line of Laura Chico with Wedbush. Your line is open. Good afternoon. Thanks for taking the questions. I just have two. Just a follow-up on the last question around PK/PD analysis. Emil, based on what you're seeing now, I do realize you're moving up to a 14 mg dose, but wondering if you could discuss maybe perhaps how you're envisioning the dosing interval during the maintenance phase. I guess, is there potential for this to kick out and follow a longer Time frequency between the two doses, as you go further out, and then I have a quick follow-up. Yeah. Right now we're just going to 7 mg up and 10 mg. If we don't get to where we know they would step one more from 7 mg up to 10 mg and 10 mg to 12 mg. We're not necessarily going to 14 mg. That would be only if we're not where we need to be. Just to be clear on that point. It's very possible as you get to higher doses loading that you could change the time. We had made the decision early on that trying to change two variables at once actually makes it very hard, and it's better for us to figure out the dose during a four-dose load. Because of the half-life of the drug, a four-dose load should get you to steady state, and every three months we think should maintain that steady state, if not accumulate a little bit. The goal of this is to kind of make dose the actual variable and not play with the regimen just yet. Once we get patients loaded and hitting our mark and efficacy in the maintenance phase, in the long run when they're loaded in the maintenance phase, we can look at whether you can space out the maintenance phase a little further. Right now our biggest goal is let's get to the dose that is safe and doing what we need with the assumption that we use four doses, which should get you to steady state drug levels based on the PK properties of the drug. That's how we're going about it right now. Laura, hopefully that answers your question. Yeah, it does. That makes a lot of sense. I guess I do have a follow-up question then just for the physician. What percent of your patients currently under care for Angelman's would be amenable to receiving monthly intrathecal administration? I guess I'm asking this in the context of how feasible is transportation and just getting them in a clinic. What proportion of your patients could feasibly go through a regular intrathecal dosing regimen? Thank you. Yeah. Thank you. Erick, do you wanna make a quick comment in that regard for your patients? Yeah, sure. It of course will depend on the medical system. Factors are country- to- country and province or state. I can speak in Canada there wouldn't be obstacles in the number of patients that require or that are scheduled, because there are provincial hospitals at different levels that would be able to collaborate and have all patients dosed under sedation. I don't think that there would be a limit in the percentage of patients that would be able to be dosed considering the need of sedation. Because if a hospital is, let's say, saturated or doesn't have- Erick, I think. Excuse me, Erick. I think they were just asking, do you think parents would not want their children to get an LP? Yeah. What fraction of patients would wanna do this is what the idea is. Oh. Sorry. Apologies. 100%. They Okay. So far, all the parents that I have spoken with, they all pretty much would go for it. Yeah. Thank you. Liz. I don't know what Liz thinks. Yeah. I have about 200 patients on my wait list to get into any ASO trial right now, and I haven't met anyone in clinic who was afraid of LPs when faced with the magnitude of the problem in Angelman syndrome and an opportunity to improve it. Very helpful. Thank you. That's it. Thank you. That's a good answer. Yeah. I'm showing no further questions in the queue. I would now like to turn the call back over to Joshua for closing remarks. Thank you. This concludes today's call. If there are additional questions, please contact us by phone or at ir.ultragenyx.com. Thank you for joining us. Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.