Good morning, everyone. My name is Gena SMID Cap biotech analyst at the Barclays. Welcome to our seventh, Gene Editing Gene Therapy Summit conference. I would like to thank all the participants, investors, companies, and especially our event team and corporate access team who made this event possible. With that, I would like to introduce our next presenters, Eric Crombez, Chief Medical Officer, Gene Therapy from Ultragenyx. Eric, thank you very much for joining us today. Great. Great to be here. Yeah. I know, you know, last week we just had a, you know, the ASGCT present, you know, quite some update last week. Maybe I'll just start with question on your several gene therapy programs. You know, first one is the DTX401 GSDIa. You know, when we look at the ASGCT update longer follow-up, you know, certainly very clear supported durability. However, when we look at the different cohorts, you know, seems there is no clear separation in terms of a corn starch reduction from different cohorts. Do you now from the hindsight, do you think you still have optimal dose and the steroid regimens for phase II, III? Yeah, no, absolutely. For our GSDIa program, we're in a traditional phase III now. That study has been fully enrolled. Corn starch is our primary endpoint there, very focused on reduction of corn starch in that study. It is a double-blind placebo-controlled trial. That's why we're really still looking at the phase I/II data, you know, for our external publications and was a presentation at ASGCT. I think, you know, it's important. It's important to continue to look at this long-term data because a big part of this and a big part of dose selection was durability. I think when we were initially looking out at the readout from the phase I/II study going into end of phase II with the FDA and other regulatory meetings, you know, you have a rather fairly limited insight into durability there. I think when going through the different dosing cohorts, I think what's great is you're seeing compelling results at all doses. While corn starch remains our primary endpoint, we are really looking at the totality of the data available to us. You know, that's total corn starch amount, frequency of corn starch, time to hypoglycemia. Also very importantly, and we do this as part of the formal part of the study with interviews, is the more subjective part of this, the stuff that's sometimes a little bit harder to measure, you know, how these patients are feeling. It's a disorder of energy metabolism, you know, we have a lot of patients who are really reporting a lot more energy, the ability to, you know, exercise, travel, some patients going back to work, and that was very important. Looking at the totality of the data, we do think the dose we brought into the phase III, roughly 1E13, is a right dose. I also think, you know, looking wholly at all of the available data for liver-directed gene therapy, I think that E13 range really is that right correct range where you're balancing efficacy and safety. Mm-hmm. Eric, can you remind us the steroid regimen? Yep. We evolved our approach with steroids. You know, certainly, you know, we've been using steroids for a long time, I think well over 10 years at this point with those initial studies in hemophilia. I will say when we brought our initial programs in the inborn errors of metabolism, GSDIa and OTC, that reactive steroid approach, waiting to see if you had an increase in LFT, then starting steroids and trying to control that response was really what was done, and that's what we started with. We evolved our approach, and I think it's fair to say that it continues to evolve with us and more broadly towards the prophylactic use of steroids. I think that does help. I do think we can do better on the immunologic front. I think controlling that immune response is important, and I do think it drives a lot of variability in all of our gene therapy programs, at least the peripherally administered ones. We're bringing forward prophylactic steroids in our pivotal trials, but we are thinking quite a bit about moving beyond that and really looking at other B-cell and T-cell depleting drugs. I see. Okay. Very good. You know, I don't know if you can share, like, what is the powering assumption for the phase III? For GSDIa, we are stratified by age. We're looking at pediatric patients separately from adult patients. The growth does come into play, activity levels, puberty, we do stratify by age and then also target blood glucose levels, really how often patients are in range versus out of range, really that focus on hyperglycemia. That is how we're randomizing. With the 50 subjects we're enrolling plan to enroll in the phase III study, I think fair to say that if we see the results we saw in the phase I/II, we're very well-powered to be successful with this phase III study. Okay. which means 60%-70% corn starch reduction at a 48 weeks, right? That's what we're seeing from the phase I/II. That would be sufficient- Yes. you know. for the powering assumption We obviously had those conversations. We had a lot of conversations with the FDA and other regulatory agencies and, you know, we have agreement that reduction in corn starch is clinically meaningful. From, I'm pretty sure you also talked to a lot of the physicians as well, like, what would they be looking for regarding the cornstarch reduction that would be considered clinically meaningful? Yeah. I think that's important. I think, you know, oftentimes you're kind of pushed to picking a number, and I think that's hard because you do see a lot of variability. Again, yes, it's important that reduction in cornstarch is our primary endpoint, and that drives a lot of this, but that's, you know, that's not really the totality of what we're trying to accomplish with this drug. Again, you know, we're really looking at, you know, how we're really establishing normal glucose metabolism for the first time here. You know, we do understand also these patients have not been able to break down glycogen to produce glucose during times of fasting or metabolic stress ever. It takes time to establish normal metabolic pathways. You know, we think that that's great progress. We see great results early on and then a lot of durability going into the out years. We really are focused on how these patients are doing overall and not just reduction in cornstarch. Okay. Okay. The other part, when we look at the second or like, you know, the data package that you plan to submit to the FDA, you also said, you know, would like to have a long-term phase I/II data as a supporting durability and approval. What kind of long-term follow-up data? You know, like, is there any particular, say, number of years follow-up you need to have? Also, is there any% of a cornstarch reduction the FDA is looking for the long term in order to deem that to be supportive? Our primary efficacy analysis period for the phase III is 48 weeks. you know, I think anytime you're gonna talk to any regulatory agency, including the FDA, I think their bias is always toward longer term follow-up and more data, and I get that. You know, we do think we see very compelling results within that first 48 weeks, so if that is the data package we intend to submit for approval. you know, that means that's 48 weeks for the last patient dose in the study. Certainly for the patients enrolling early in the study, we will have longer term data, and we will submit that, and then we will have, obviously, you know, four, five, six years plus for data from the phase I/II study. I think in totality, we will have a very good idea of durability. We had quite a few patients dose in our phase I/II at the dose we took into our phase III. You know, I think as long as durability is holding up, and I think, you know, it's fair to say with the data we presented ASGCT, we're seeing good durability, I think that should be sufficient. In general, though- Okay. We do wanna follow... Sorry, go ahead. Oh, sorry. I think, you know, durability is important for us beyond the conversations we're having with regulatory agencies because, you know, you know, I, you know, to me, even if it's 10, 15, 20 years down the line, you know, these patients, if there is dilution of the transgene due to growth in pediatric age ranges, hepatocyte turnover, you know, we do need to monitor them and understand that, and make sure they're not at risk for, you know, a very significant hypoglycemic event. Our intention is to follow them for the long term, you know, beyond the commitments we make to regulatory agencies. Okay. That makes sense. Your second program, the DTX301 in OTC deficiency, also, you know, the ASGCT update, phase I/II also support durability now with up to 5.5 year follow-up, the rate of responders and complete responders were maintained. Now when we look at the, I think the primary endpoint is the complete responders, that's like four out of 11, when we saw the phase I/II data. The, maybe also again, you know, asking from, you know, did the FDA set a minimal threshold for the rate that they were looking for? There's one question, is the, you know, approvability for the rate. The second is the, again, asking from the doctor perspective, clinical meaningful, what is the rate for clinical meaningful perspective? Again, and I think that that's great work we did with the FDA and other agencies because we weren't really forced to set that threshold. We didn't see a threshold, and we are looking at kind of an overall responder rate. That's the responders plus the complete responders overall. Then we will look at complete responders, those patients who are able to completely discontinue alternate pathway medication and come off of their protein restricted diet versus responders that can decrease that by half. So we put that in an overall response category for the primary endpoint and then break it down in the secondary. The second primary endpoint, it's also important, and that's maintaining ammonia control. Ammonia control was used as the basis of approval for some of the other alternate pathway medications, that is a clinical endpoint at this point. Again, we are looking for approval, not a biomarker likely to predict. We, we think it's important there. We are looking at non-inferiority just because you do need to control these patients' ammonia levels, and you can do that during times of good health when these patients are under good metabolic control. The problem we see with current standard of care is that they're still having metabolic crisis. They're still having quite a bit of neurocognitive damage, and we think by replacing the missing enzyme with the use of this transgene that the best way to prevent metabolic crisis in the future is by establishing normal function of the urea cycle. Again, with power, we are stratifying by gender because this is an X-linked disorder, and then also ammonia control because, even with the best care, the best use of alternate pathway medication diet, you can't always control ammonia levels. That's our stratification. Again, similarly to GSDIa, if our results from the phase I/II study are consistent for the phase III, we will have a successful phase III study. Mm-hmm. For this one, you do have a co-primary endpoint, and you did mention ammonia control as a non-inferiority. Like, how does the stats work? Is that the splitting out for two independent events, or is there a statistical hierarchy you have to reach, say, complete responses, that hit that endpoint, then we can look at the ammonia control? We're looking at both of them together. We are looking to win on both, looking for superiority for the overall responder rate, yes, looking for non-inferiority. Superiority for ammonia would be very hard because again, We don't really tolerate ammonia levels above the upper limit of normal, and Obviously, if you get too high, you can start to slip into coma and really having, you know, irreversible neurocognitive damage there. During wellness, you can do a pretty good job of achieving that. Superiority would be very difficult. Looking at non-inferiority, and that's really just setting the margin there, really how much, if you will, plus minus on those ammonia levels you can have to call it comparable. Very helpful. Now quickly just on the DMD gene therapy. I know follow Sarepta outcome. You were panelist there, and we will discuss more later this afternoon on this topic. You know, maybe your latest thoughts on your DMD gene therapy. By the way, I'm pretty sure you saw Sarepta news, you know. Maybe, you know, high-level thoughts and then, also the read-through to your DMD gene therapy program. Yeah, you know, it's interesting. I think, you know, as you mentioned, I'm serving as the industry representative on the advisory committee, really with the job of representing all of industry there. Lots of work with Sarepta, lots of work with the patient organizations going into that advisory committee meeting. I think really looking at the FDA briefing book, I think it was a very good outcome coming out of that advisory committee meeting. I think, you know, obviously, it was a favorable vote, but it wasn't an overwhelmingly favorable vote. That was a question in my mind is, you know, what does this mean for the FDA reviewers? I think the clarification for today, it's interesting. I think it's definitely a win for accelerated approval, because, you know, this outcome, while absolutely important for patients with DMD, it is important for accelerated approval for rare diseases. It's important for gene therapy. I think that's important that, you know, they're recognizing dystrophin there as a surrogate likely to predict. Obviously, looking at that data, the results are more clear in four-five-year-olds, and if they go that route, it seems to be a middle-of-the-road route. Certainly, you can get started with that group of patients. Luckily, that confirmatory trial is already fully enrolled, it wouldn't be a really large delay with getting those results and being able to broaden that label. I think interesting information today, and I think maybe fair to say a middle-of-the-road approach. For our program, we do have our DMD program. It's currently preclinical. We do wanna make sure that if we're, you know, bringing forward a program that's not gonna be first or second or potentially second into clinic, that, you know, we have a really solid understanding of this transgene capsid, any optimization we can do, and then, you know, bringing forward this program in our manufacturing facility that we're building outside of the Boston-Cambridge area, moving to the Pinnacle PCL manufacturing process, which really does give us a much better handle and control over cost of goods and, you know, with the doses that are needed for muscle-directed gene therapy, I think that's very, very important. With this, if ultimately this is approved by a surrogate likely to predict, that does give a pathway for other programs to come along. That means you don't need to do a very large clinical endpoint-based trial. I think this type of approach and this type of approval doesn't hurt other development programs. It's very enabling for follow-on treatments, whether that's gene therapy or something else. Okay. I know we don't have too much time left. I do wanted to ask you about the Enduranc program. If the approval on aligning U.S., ex-U.S. protocol, enable Ultragenyx to harmonize those ranges in the U.S., so the with those being used in the ex-U.S. Wanted to ask, did FDA see additional data before making this announcement? Was that the decision was based on the safety data alone, or also taking into consideration of efficacy data? No, I think it's fair to say they really saw all of the data that we had available, you know, during these conversations to share with them. They really did see and now have a very deep understanding of the safety and efficacy data. You know, really productive conversations that built upon themselves, and I think, you know, great that we're able to move forward. Yes, it was absolutely based on a conversation of the totality of the safety and efficacy data we have today. Okay. does that means you can use the protocol you lay out for the ex-U.S. now just can apply it to the U.S. as well? are you only enroll the patient in the extension cohort, or are you also continue doing the dose escalation in the U.S.? Right now, we've really moved beyond the initial dose-finding cohorts, if you will, and really now moving into expansion cohorts, really with the intention of confirming the dose we'll bring into phase III. I think that's an important, you know, evolution in our understanding of this drug, and it's not really just wide open traditional dose finding, but really now with these expansion cohorts, dose confirmation for phase III. Okay. That, which means the U.S part, the opening up, most of the patient will be enrolling for the expansion cohort. Correct. Okay, good. one last question. Any FDA feedback on functional endpoints? So, uh- You have, like, many different ones, CGI and Bayley for, Vineland and, ORCA, CA measurements. Like, any feedback on any particular measurement the FDA would prefer or would be the totality? I think it's fair to say we're looking very, very closely at the Bayley. I think the results there are compelling. I think the results, you know, we've published to date, you know, show real benefit there, a real positive signal. We've said we'll share an update on that data in the second half of this year. Again, that data was shared and discussed with the FDA in the context of getting restarted in the U.S. You know, we didn't have that conversation in the context of an end of phase II and really what will be our primary and key secondary endpoints. Obviously, we're thinking quite a bit about that. Yes, there's been discussions, but we, you know, we'll be going back and having this conversation in the context of the phase III design going forward. When would that happen? Uh- Going back to the FDA to discuss? I think, in the relatively near future, once we get the data from these expansion cohorts from ex-US and US, make sure we understand the dose strategy we're bringing forward to phase III, then we'll go back to the FDA for that, for that specific end of phase II conversation. Okay. I just want to confirm, right now you actually prefer Bayley-4 right now among all the measurements, right? I think the data's compelling there. I think that's where we're spending a lot of time thinking about this. I guess we don't wanna get ahead of ourselves and, you know, really kind of lock in decisions before we've seen all of the data out of the expansion cohorts. I think it's fair to say that we've done a lot of work on the Bayley. I think it's fair to say the FDA has a good understanding of the Bayley. It is a well-accepted and used tool in clinical practice, I think it could be a very good choice. Okay, great. Well, thank you very much, Eric. We look forward to our discussion later this afternoon. Thank you. Great. Thank you.