Ultragenyx Pharmaceutical Inc.

Good afternoon and welcome to the Ultragenyx First Quarter 2025 Financial Results 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 the call over to Joshua Higa, Vice President of Investor Relations.

Thank you. We have issued a press release detailing our financial results, which you can find on our website at ultragenics.com. Joining me on this call are Emil Kakas, Chief Executive Officer and President, Eric Harris, Chief Commercial Officer, Howard Horn, Chief Financial Officer, and Eric Krambes, Chief Medical Officer. I'd like to remind everyone that during today's call, we 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.

Thanks, Josh, and good afternoon, everyone. In the first quarter, we continued to make meaningful progress across one of the most productive commercial and development pipelines in rare diseases. Our commercial team delivered a strong quarter that puts us in position to have another year with meaningful revenue growth. Our early investments in high-performing teams have helped generate substantial revenue growth. while we commercialize our products outside of the United States. At the same time, we are preparing to launch our next set of programs in the U.S. and around the world. Our development teams have advanced our large and late-stage programs as well. For the UX143 and Osteogenesis Perfecta, patients in the phase three phase have now been enrolled for at least a year, and the process has begun to clean and lock the databases for our second interim analysis. For GTX102 and Angelman syndrome, the Phase III is enrolling efficiently at sites in the United States, Canada, Japan, Germany, Poland, and Spain, and data are expected in 2026. For DTX301 and ornithine transcarbamylase deficiency, or OTC, the Phase III study completed enrollment in the first quarter and is on track to read out data over the next year. For UX701 and Wilson disease, the study is now enrolling the fourth dose finding core that will enable dose selection and transition to the pivotal stage. At the same time, we're working on two separate BLAs, one currently under review and a second to be submitted. The GTX 401 for GSD 1A BLA submission is on track for mid-2025 after successful completing the PPQ runs, the qualification laws essentially, at our manufacturing facility in Bedford, Massachusetts. The UX111 for San Filippo syndrome BLA under review by the FDA is progressing on schedule as expected. It's not our standard practice to go into the details of regular interactions, but I think it's meaningful at this current time for investors to be aware that our interaction with the FDA on the UX111 BLA review thus far remain on track. Last month, we had our mid-cycle review meeting that occurred on the standard timeline. We also know the inspections of the manufacturing facilities and clinical sites have been scheduled according to normal cadence and are currently underway. We remain on track for the BDUFA action date of August 18. Going forward, we don't plan on giving the details of all our regulatory interactions, but we did want to share enough detail for you to remain confident as we are that the UXDLA review is progressing according to plan. With that, I'll turn it over to the rest of the team to share the details of why 2025 will be a transformational year for Ultragenyx. Eric, I'll hand it off to you to go through the commercial team's execution in the first quarter.

Thank you, Emil, and good afternoon, everyone. In the first quarter, the commercial organization continued building on the momentum that we saw at the end of 2024, starting with Chris Vita in Latin America, where we lead commercial operations. Our team generated approximately 40 new start forms that led to approximately 40 patients on reimbursed therapy. We now have approximately 775 patients on commercial product in the region, as the team continues to exceed our expectations for CRISP VITA. Physicians in the region consistently tell us how well their patients feel on therapy, which has led to an increasing number of doctors writing prescriptions for multiple patients. We expect growth in the region to continue following the successful negotiation of reimbursement from the Brazilian and Mexican authorities, which are the two largest payers in the region, and continued expansion in other Central and South American countries. In the United States, our partner, Kiara Kiran, is leading commercialization for Chris Vita. The first quarter 2025 revenue was supported by increasing new start forms, and new patients on reimbursed therapy. It is fulfilling to see that adults around adult demand... It is fulfilling to see that adults around... Adults have exceeded the... Make up more than half... Make up more than half of patients on therapy considering the skepticism around adult demand at launch. We expect 2025 US per speed of revenue to continue growing as they work to identify new pediatric and adult patients with XLH and convert them to treatment. Moving on to the Jovi in the United States, growth of new start forms in the first quarter continued to steadily increase, just as we have seen in prior quarters. Our team generated approximately 30 new start forms and added approximately 25 new patients to reimbursed therapy. This brings the total since launch in 2020 to almost 600 patients on reimbursed therapy. The split between pediatric and adult patients continues to be approximately 65% Peds and 35% adults. Also, the number of new prescribers continued to grow in the first quarter with approximately 270 unique prescribers. For the Jovi across the EMEA region, there are over 260 patients treated under named patient sales across the region. The majority of demand is from France, but we are receiving an increasing number of requests from other countries within the EMEA region, including the Middle East. The demand for this product is quite strong in this region, especially given we are not actively marketing the therapy and simply responding to named patient requests. I'll close with a few comments on FKESA, which we began commercializing in our territories outside of the US in 2023. In the EMEA region, we have patients on reimbursed therapy from the majority of major countries. We now have treated approximately 250 patients, adding more than 50 since the beginning of the year across 15 countries in the region. This is the result of our commercialization efforts and response to name patient requests as we continue to successfully navigate the country-by-country pricing negotiations. In Japan, the team continues to build on the launch momentum following the pricing and reimbursement approval that we received last year. In Canada, we are continuing pricing negotiations with government health authorities and have secured reimbursement agreements with three of the four major private insurers. Over time, we expect FQs and revenue to contribute more meaningfully to total revenue as we continue to successfully launch this important product outside of the United States. As I have mentioned on previous earnings calls, we continue to expect quarter-to-quarter variability in revenue, primarily due to uneven ordering patterns for Chris Reeder and LATAM. but we remain confident in the growing underlying demand for all of our products around the world. With that, I'll turn the call to Howard to share more details on our financial results and guidance.

Thanks, Eric, and good afternoon, everyone. I'll focus on first quarter 2025 financial results and guidance for the year, starting with revenue. In the first quarter of 2025, we reported $139 million representing 28% growth over the first quarter of 2024. CRISVITA contributed 103 million, including 41 million from North America, 55 million from Latin America and Turkey, and 7 million from Europe. In total, this represents 25% growth over 2024. If you focus on Latin America and Turkey, where we are responsible for generating sales, this represents 52% growth over 2024. Turning now to Dejolvi, it contributed $17 million, consistent with its expected steady growth trajectory. Evkiza contributed $11 million, as demand continues to build following launches in our territories outside of the United States. And Mepsevi contributed $8 million, as we continue to treat patients in this ultra-rare indication. Total operating expenses for the quarter were $282 million, which included R&D expenses of $166 million, SG&A expenses of $88 million, and cost of sales of $29 million. Operating expenses included non-cash, stock-based compensation of $40 million. For the quarter, net loss was $151 million, or $1.57 per share. As of March 31, we had $563 million in cash, cash equivalents, and marketable securities, which reflects $45 million in cash payments made for two milestones during the first quarter of 2025 that were achieved in the fourth quarter of 2024. Specifically, $30 million for a GTX 102 Phase III study milestone and $15 million for an Evtisa sales milestone. In the first quarter of 2025, net cash used in operations was $166 million. Recall, in the first quarter of the year, we typically use more operating cash than in the subsequent three quarters because it includes items like the payment of annual bonuses. In addition, first quarter net cash used in operations also included the $30 million GTX 102 development milestone payment I mentioned earlier. Net cash used in operations is expected to decrease in the remaining quarters of this year and is expected to total less than what we used in 2024, as we continue on our pathway to full-year gap profitability in 2027. Shifting to revenue guidance for 2025, we are reaffirming the guidance we gave in February. Total revenue is expected to be between $640 and $670 million. which represents 14 to 20% growth over 2024. Drivers include increasing demand for our products in Latin America, continued penetration of the pediatric and adult XLH markets in the U.S., and growth from Mefkiza in Europe and Japan. CRISVITA revenue is expected to be between $460 and $480 million, which includes all regions and all forms of CRISVITA revenue to Ultragenyx. This range represents 12% to 17% growth over 2024. Dejolvi revenue is expected to be between $90 and $100 million, which represents 2% to 14% growth over 2024. As in prior years, our Dejolvi projections represent a blend of faster growth in countries where we commercialize and lower growth in countries where we respond to name patient requests. Lastly, with respect to tariffs, the landscape continues to evolve. We are actively monitoring and evaluating multiple potential scenarios. Based on what we see currently, we do not expect to have a material exposure for any of our products, including Grisfita. With that, I'll turn the call to our CMO, Eric Krambes, who will provide an update on our key clinical data readouts expected this year.

Thank you, Howard, and good afternoon, everyone. I'll provide some brief operational updates on our late-stage programs and review our upcoming clinical milestones. Starting with the UX143 for the treatment of osteogenesis imperfecta, the Phase III orbit study continues to progress well, and as we noted earlier in the year, the safety profile is similar to what was observed in Phase II. Based on the Phase II data we previously shared, we are confident that the study will show a clinically and statistically significant reduction in annualized fracture rate, at either the second interim or final analysis. The ORBIT and COSMIC studies will both have an interim analysis mid-year after all patients have been on therapy for at least 12 months. The data readouts will be led by ORBIT, meaning that if ORBIT clears the p-value threshold of less than 0.01, we will look to see if COSMIC has cleared the same p-value threshold of less than 0.01. If ORBIT progresses to full study completion in the fourth quarter of this year, COSMIC will also continue to a data readout to align with the ORBIT data readout without spending alpha at this interim assessment. Moving to GTX 101 for the treatment of Angelman syndrome. We have set an ambitious goal of enrolling a 120 patient pivotal study in less than one year. I'm proud to report that we are on track to achieve this goal and we are actively working with sites in the US, Europe, and Japan to enroll patients. We have also made progress finalizing the Aurora protocol, which will study younger and older patients and those with other mutations. We expect to take this protocol through the regulatory process and begin enrollment later this year. Next, DTX-401 for the treatment of glycogen storage disease type 1a. In our press release today, we shared some of the additional crossover data that will be included in our BLA filing mid-year. During the crossover period, patients demonstrated even greater reductions in total daily cornstarch at their last visit compared to baseline in both the ongoing DTX-401 group and the placebo crossover to DTX-401 group. Patients in the DTX-401 group demonstrated a 60% reduction in daily cornstarch at their last visit with a mean follow-up of 120 weeks. This is a substantial and continued reduction compared to the 41% reduction in daily cornstarch observed at week 48. Patients in the placebo to DTX-401 group demonstrated a similar 64% reduction in daily cornstarch at their last visit, where the mean duration on therapy with DTX-401 was 69 weeks. Patients in both groups have demonstrated statistically and clinically meaningful reductions in daily cornstarch requirements demonstrating continued benefit from this gene therapy over time. DTX 401 also continues to demonstrate a consistent and acceptable safety profile with no new safety signals identified. The manufacturing process at our Bedford, Massachusetts facility is going well, and we recently successfully completed our process performance qualification runs. While the tech transfer from a CDMO to our facility was done quickly and efficiently, it did impact our BLA submission timing. We were able to capitalize on this opportunity to collect more clinical data, resulting in an even stronger clinical and CMC filing package that we will submit to the FDA mid-year. Finally, I'll touch on UX701 for the treatment of Wilson disease. As noted in our press release today, we have recently begun enrolling patients into a fourth dosing cohort at a dose of 4E13. These patients will receive a new immunomodulation regimen with rituximab and tacrolimus in addition to the corticosteroid regimen used in the previous cohorts. We expect that the combination of enhanced immunomodulation regimen and a moderately higher dose could achieve the broad response needed to select a dose to take forward into the pivotal stage two of this study. Also noted in our press release today, The pivotal Stage 2 portion of the protocol was amended to a 52-week randomized open-label active control design. The open-label design allows for patients and investigators to be more comfortable with this continuation of standard of care, consistent with our experience in our other metabolic gene therapy programs. The Stage 2 primary endpoints are largely the same as before, but instead of comparisons to placebo, they are now compared to the active control arms. Specifically, we will be looking at the change in 24-hour urinary copper from baseline to Week 52 and percent reduction in standard of care by Week 52. I'll now turn the call back to Emil to provide some closing remarks.

Thank you, Eric. Over the first part of the year, we've made tremendous progress executing on all fronts. Patients in both UX143 for osteosimperfective studies have now enrolled for at least 12 and this enables our teams to start the process of cleaning and locking the databases that will be shared with the Data Monitoring Committee in the next few months. The feedback we hear from investigators with patients in the Phase II portion of the ORBIT study gives us confidence the treatment effect of cefuzumab and osteogenesis perfecta is transformative for these patients. In closing, we expect 2025 to be the most productive year in our company's history, with the commercial organization generating $640 to $670 million in revenue, and the development organization managing one BLA under review, a second to be submitted in the middle of the year, and multiple phase three studies enrolling or reading out data, we are in prime position to lead the future of rare disease medicine. With that, let's move on to your questions. Operator, please provide the Q&A instructions.

Thank you. We'll now be conducting a question and answer session. If you'd like to ask a question, please press star 1 on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star 2 to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. In the interest of time, we ask the participants limit themselves to one question and one follow-up and re-enter the queue for additional questions. One moment, please, while we poll for questions. Our first question is from Yaron Werber with TD Cowan.

Great. So, thank you so much for taking my question. You know, not surprisingly, it's going to be about citrusumab, the second interim analysis. And sort of one question in two parts. Maybe the first one, Emil, you've talked recently about dispersion in the study. And that's something that when we look at the prior data in the Phase II, the dispersion, is not really shown. We can tell that there's variability in how many fractures patients have at baseline. So can you maybe explain to us what do you mean by dispersion and maybe why it's important? And then secondly, when we look at the 67% fracture reduction, if I recall correctly, that was at around six to seven months. Can you give us a sense kind of what he was saying when he was at 14 months, the latest cut that was at ASBMR? Thank you.

Sure, Ron. Thank you. I don't know if I actually use the word dispersion, because that's like a statistician term. I usually mention variation, that there is a variation in the analyzed fracture rate at baseline. And we know we have people who can have more than three fractures a year, or any fractures greater than three and some less. And we stratified in the trials that those with a greater than three would be stratified equally between the treatment and placebo group, as would the ones below that. But how it's distributed can have some impact on the probability of success just because variation is what really affects p-values. So we haven't talked through that distribution or shown it, but there is a fairly wide range of fractures baseline. Now, the statistical method we're using, the negative binomial, will capture the AFRs at baseline as a covariable, meaning we'll help correct for that in the way we analyze it. which help assure that it doesn't have a substantial impact. We're also stratifying by age in the trial. So we're doing a number of things which will help reduce variation, but there is a lot of variation in severity and fracture frequency, and we think we've done what we can. But that might be one reason why you might not hit IE2. We think we have a good shot of hitting IE2, based on everything we know. But we are very strongly positive on the trial, whether at IE2 or the end this is going to be successful. So let's talk about the fracture reduction. We announced phase two data after six months or so, and showed a 67% reduction with a p-value of 0.04. Now when we did the 14 month cut of the same 24 patients, we had the same 67% reduction in fracture frequency median, and the p-value though was 0.0014. So you might be wondering, well how is the number the same? I would look at this and think of it as a line of accumulated fractures, the accumulated fractures in one group is going up at a steep rate, and the slope of the other line is only 67% less. The two lines are running apart from each other. If you cut the two lines earlier, they're not as far apart, but if you wait for those two lines to progress further, they're further apart. The slopes are still 67%, the same treatment effect size, but the p-value is better. So what's happening at interim one is that they may not have separated far enough yet, and it only would have happened if we had a lot of fractures. But by the second time, we'll have run longer that we should have much better separation. So from that analysis, it suggests that we could hit it at IE2. It's a reasonable shot. Now, we did do an analysis of our Phase II data for those that have heard this from me. We did take the same data and analyze the patients as if their prior year was on you know, placebo and compared to their current year on treatment. And with the negative binomial, you get the same 60s, mid-60s percent kind of reduction and, all right, with a good p-value. So, just to be clear, if you do it by the method we're using in Phase III, you get a very similar result. Just because some people wondered whether the different statistical approach would matter. So, variability is an issue. Dispersion or a statistical version of it we could go into. I think the key thing I would say is that I think we have plenty of power to succeed in the study whether it's IE2 or at the end.

All right, let's go on.

Our next question is from Kazin Amak with Bank of America.

Hi, good afternoon. Thanks for taking my question. Emil, I also have a question on OI. This would be if the study moves to a third interim read, what's your view of the likelihood of success? You've talked now multiple times about confidence in the molecule overall, and we would agree that the drug is active. But if the study moves to the third interim, what would be a reason to be concerned that it would not work at the third interim? Thanks.

Right. Well, it won't be, the next assessment is the final assessment for the study, and that p-value threshold will be 0.04. So, it would be a lot easier to hit 0.04. So, we think that we will hit one or the other based on our experience, what we've seen. I don't think we could miss the 0.04 at that point with 18 months of time. But as always in rare disease programs, the other, the thing you always are battling is variation. variability in patients. But based on the profound difference in bone marrow density change that we see that happens within two to three months, and the fracture rate effect happens within two to three months, we feel pretty good about IE2 hitting, but confident about overall steady hitting even at the end, if not at the IE2. So I can't tell you a reason why, but variation is always a thing that can create complexities. But given that the patient's The program is 159 patients. That's a pretty large study. And the data we're talking about before was 24. So I think we've got a lot of power in there. But we've done everything we can to manage variations. So I feel good about we'll hit it this year either at 0.01 or 0.04 after 18 months.

Our next question is from Gina Wong with Barclays.

Thank you for taking my questions. Maybe I will just switch gears a little bit, you know, the non-fundamental questions. I think it was the reason CBAR nomination of Vinay Prasad, and I think there is a lot of uncertainties. We saw massive sell-off in the biotech sector. And so, Abigail, maybe you wanted to get your thoughts like where do you see that could be potential impact to specifically in a rare disease space and how do you deal with or what would be the strategy you have dealing with this situation? And there's still open questions, a lot of uncertainties there. And my second question is also go back to the OI. I think a recent discussion we had, you did mention that like over maybe 80% of patients have a baseline bisphosphonate. And then the washout period, in the late enrollment period, you did skip the washout period. So would that be a concern regarding, say, the placebo factory picking up at some point? Would that have a delay rather than, say, 12 months? Would that need a little bit longer time so that we can see the placebo on the factory start to pick up?

Very good. So, yeah, the CBER appointment, you know, we don't think was a good choice as someone who has argued against accelerated approval for cancer programs, and that may be a concern. I think we'd have to anchor back to the fact that Kerry has been talking about the importance of rare disease approvals and thinking how to improve and accelerate the process or reduce the time of development. So, we'll have to anchor to that discussion and point he's made and see what Prasad does. For our own program, for UX111, we have lots of clinical data in the program. I'm less concerned about it because, in fact, we have clinical data showing efficacy in addition to the biomarker data. And so I think for us right now, we're not concerned. But I think for industry at large, it would be important for accelerated approval to be available for a lot of the gene or cell therapies, and it would be important that McCary's public commitment to try to move these things forward. It's something that he followed through on. How Prasad will do that, we don't know, but I think the FDA is very important. The industry supports the FDA in their mission, and we just hope that they continue to make good decisions. On the second question. More than 80%, maybe 89% or something like that were on bisphosphonates in the study, right, Eric? Correct. Yeah. And the washout timeframe, you know, is in the one to two-year period. So we'd expect the placebo patients to have steadily declining bisphosphonate effect and therefore a steadily potentially increasing fracture rate as their bone marrow densities decline. But we don't think that effect is really a meaningful effect compared to the dramatic effect on bone marrow density that's going to happen with citruzumab, right? Where for the 5 to 12 group, we had a 29% increase. The bone marrow density improvement, the effect on the other groups will not be nearly so large. So what it would do is both groups would have a loss of bisphosphate effect over the period. But remember, citruzumab arm will also have some anti-resorptive effect from the drug itself. So if anything, what this will do is increase the rate of separation as time goes on and improve the power of the study the longer it goes.

Do you have anything else to add to that, Ethan? Just that we didn't count on this when we were designing the study and powering the study. We did not account for that effect. So, in any sense, that could be considered an upside.

Very good. Thank you.

Our next question is from Salveen Richter with Goldman Sachs.

Hi, this is Lydia on for solving. Thanks so much for taking our questions and congrats on all the progress. Just maybe another one on the truth. Could you just discuss how you plan to message the outcome of the interim to the street and whether you intend to share any data with this update? Thanks so much.

Yes, so when we the. DNC presented the information on orbit. If it's positive, they'll inform us and we will inform the street of the results. If they inform us that the study needs to go to the end, we'll also inform the street that the study is continuing to the end. If you haven't heard from us because the decision hasn't happened yet, and a decision either is moving forward to the final assessment or it's ending at the interim will be clear. We haven't set what all the data might be in or not in that release. Different from interim one, we are having to fully clean the database for potential filing from that data set. So the timed data would be faster than we have said for the IE1, where we had only partial lock and we had to continue the trial. So it would be relatively soon after we talk about data. Now, if IE2 is positive, then the cosmic study will be evaluated. If orbit is negative, then we won't unblind the cosmic data and we'll wait. for both studies to go to the next assessment. Okay?

Thanks so much.

Our next question is from Anupam Rama with J.P. Morgan.

Hi. Thanks for taking the question. This is actually Malcolm Kuno for Anupam. So where are you on your enrollment curve for the Angel Wind program, and have you opened all of the global sites for the program yet?

Well, I'll ask Eric to comment on that.

Yeah. So, like we said, you know, our plan is to fully enroll that study this year. We are committed to that. We have really prioritized that and leveraged the experience we had with OI and really enrolling, you know, for us, for rare disease, a relatively large pivotal trial. So, we certainly want to do this as quickly as possible. And yes, our global sites are active and beginning to screen in those patients. So, all sites active.

Excellent.

Thank you. Our next question is from Kristen Koska with Kanter.

Hi. Good afternoon. You talk about potential variation factors. I wanted to see... color about how you're thinking about the age of the baseline. I know investors tend to focus a lot about the types of OI, but based on some of the BMD data, you've shown that the effects could be even superior the younger you treat. And I know the ORBIT trial has a range of about 20 years. So is there anything you're able to share?

I don't think we shared the exact enrollment, but the majority of patients are going to be pediatric and are relatively limited number of older patients. We're including them in order to allow us to label for adults as well off that study if there's any questions. But the majority of the patients are going to be in the pediatric age range for the program. Is there anything else you think we could offer, Eric?

No, I think that covers it.

Thanks. And then just to clarify, if IA2 is, if it does hit the analysis, will you also be announcing the same day whether COSMIC was successful as well, or will those updates be separate? Thank you again.

We haven't said. It depends. They're not happening. The reviews of both programs are not happening the same day. One will happen and then the other. So we haven't said yet whether we'd have them both the same day or not. We like to keep you guessing a little bit, right? Why make it too easy?

Our next question is from with Citi.

Hi, thanks. Have you commented at all on the distribution of the types for OI for 1, 3, and 4 for the phase 2 versus the ORBIT trial? And then also, this is a very specific question, but what exactly is the tolerance on these p-values? I mean, we're talking about some pretty small numbers here. So, I mean, hypothetically, if it's like 0.011 on the second interim, is that a fail or a win? I mean, I think I know, but I'm not sure, actually. So I'm just curious if you could clarify that level of detail and whether you were ever told the p-value for the first one, the first interim. Thanks.

So on the OI types, I think we've disclosed before that in the In the Phase 2 study, there were seven Type 3s and 4s and 17 Type 1s. And then because the doctors were then impressed with the results, then they were interested in bringing in their more severe 3 and 4 patients. So we ended up with more Type 3s. About half the patients are Type 3 and 4 are approximately there in the study. So it's definitely an increase in Type 3s and 4s in the Phase 3 study than they were in the Phase 2 study. All right. Now, for tolerance, we haven't set that like how many sig figs of significance. Honestly, I don't have an answer for you, but I would say if it's like 0.015 or 0.016, that is not less than 0.01, right? So, that would be considered a miss at this point, which means you could be very close to a very good result and still miss and go to the end of the year, which is why we shouldn't overreact if there's an issue. So, that's the basic tolerance question. The last one was whether there was a p-value, and the other is we haven't provided a p-value. We were not aware of the p-value, nor provided one in the interim, the first interim. We were just told that the study was continuing and no result. So what we know from the prior analysis of Phase 2, though, is that the p-value was, you know, 0.014 at 14 months. We think there's a reasonable chance of hitting IE2, pretty good chance of hitting IE2, and a much better chance of hitting IE2 at the 0.01 threshold than there was at IE1 with 0.001. All right, thank you, Galt.

Thanks.

Our next question is from Joseph Schwartz with Lear Inc.

Hey, all. This is Will on for Joe. Thanks for taking our question, and congrats on the progress this quarter. So one for us on Angelman. Now with three ASOs that are in or nearing civil development, including the one from Roche that was recently revived, are you thinking about the evolution of this market? And do you see room for multiple treatment options? And how do you think these assets could potentially further differentiate themselves? And how do you think patients are going to be making decisions from a clinical trial or commercial therapy perspective? Thank you.

Thank you. Well, you know, we're not usually going to be working in competitive space with a lot of products in the same space. This will be a new thing. Usually we're working on first-error treatments that are by ourselves. It's definitely a different space. I would say in the regard of these ASOs, ultimately the most potent and effective drug will be the one that will tend to dominate. But that doesn't mean there might not be a place for other molecules in the space as well. I think they're very similar in terms of them being intrathecally administered ASOs, but I do believe our drug is the most potent and has shown that, and I think we've shown the best long-term data, continuous improvement over long periods of time that has been shown for the INS molecule. The Roche molecule is sort of coming back into development. I am not concerned about it. I think that that drug is even less potent. and has other questions, Mark. So if there's more than one out there, I think it will depend on efficacy and what people can show. I do think that we have, because we expanded our Phase II study and we have almost 70 patients on drugs, that we're going to have a pretty big body of kids that have been on drugs several years. I think how those kids are going to doing are going to be probably even more impactful than the Phase III study. That will be what people want to see. What's my future like for my kid if I'm on this? From some of the early patients on there, the first one that actually had words, she had a few words in the first year, but now she's speaking a few dozen words and has continued to gain ground over time. So I think that experience will be really important. I do think we're in the best position to be the leader in the ASO space. And my hope going down the road that the top three ASO treatments will be our first product, then our second improvement, and then the third next gen that comes out. And because we intend to be the leaders in the engagement.

Our next question is from Lisa Baco with Evercore ISI.

Hi, thanks for taking the question. I just wanted to clarify, sorry to ask so many questions on citruzumab. Can you give us a little greater sense on where you are in terms of timing, what happens from here to data? And then I just wanted to understand, follow up on an earlier question, if the data reads up positive, do you say it's positive and then take some time to analyze the data and come back to us with the data, or is that all in one press release? Thanks.

Yeah, so on the timing of data, because I think people may, some people may have had an unrealistic expectation that you would clean, lock, and analyze the data in a couple weeks or something. But this is an international phase three study, and this clean and lock is the entire data set, not just the primary endpoint, the whole thing. Because if it's positive, we need to go straight to preparing a BLA following. So there is normally, it takes a phase three, around eight weeks of an international study to clean and lock a database. Plus there would be some time to analyze and have a DMC meet. At the time we find the result, there will be a much shorter time than we had before in terms of seeing what the data are. We haven't yet precisely said whether we'll disclose it together at once or whether it would be an initial read and some further. So we're going to leave that open right now. But our expectation is that it will be sooner to getting the top line data than it would have been in IA1 where we had some other questions. So hopefully that gives you an idea, Lisa, of how it's going to flow.

Okay. So I don't understand what took the IA1 a little bit longer, just to understand the differences there. That's my final question. Thank you.

Yeah. What happened to IA1 is that even if the interim was positive, the regulatory authorities wanted to have the majority of patients have at least 12 months of data. So we would have had to keep running the study for a couple months. In other words, if I wouldn't hit, we'd say, oh, we're far enough along. And so we would then continue collecting data for a couple months until more than half the patients had 12 months of data. And then we would have started, and we've been doing all the final visits and cleaning and locking at that time. So there would have been a delay before we clean and lock, so you wouldn't be able to see the data for not just two months, but probably three to four months. because we'd have to clean and lock it. So the timeframe here is much faster because we're going to clean and lock the whole database this time, and we would be able to release top line data sooner than we would have at IE1.

Our next question is from Luca Issy with RBC Capital.

Oh, great. Thanks so much for taking my question. Congrats on the progress. Maybe just one more on OI just to be super, super clear. In a scenario where you actually don't hit at the second interim look, will the DSMB share with you the p-value? Just wondering whether you will have a sense of whether you missed by a narrow margin or not. And then maybe related, is it fair to assume that the PRV for OI is possible only if you hit a second interim look? Even my understanding is that you need to get approved by the end of 2026 in order to get the PRV, given there's sunset in that program. Any context there? Much appreciated. Thanks so much.

Yeah, so if we don't hit it, we'll just find out that the study is continuing and we didn't hit it. We will not get any T values. We won't know if it's closed. We do have PIG designation, and we'd have to get approved by October. So whatever timeframe we file would have to be within the timeframe to get approval by October. Obviously, by 2, it's easier. If we have to go to the end of the study, then the time to file would have to be much shorter and the review rapid. But I would also point out, too, we do have breakthrough therapy designation for this program. So I think there are reasons why we could be able to accelerate things if need be. But our goal would be to get this filed in time to get a third PRV. Short of that, we certainly have already potentially two PRVs in place if 111 gets approved for San Filippo and if the GTX 401 gets approved for GSD 1A. So I don't think there's anyone with potentially three PRVs still in play without the reauthorization. I do believe the bill will get reauthorized I think we've had assurances that is true, but I think right now there's so many other matters that are top of mind in Capitol Hill that that one will take a little while before it will come up.

And to clarify, the 143 PRV is in October of 2026. We need approval by October 2026. Right. Next question. Thanks, Operator.

Our next question is from June Lee with Truett Securities.

Hello, good afternoon, and thanks for taking our question. This is Mehdi on for June. So I go on OI and follow up Iko's question on composition of OI types. So do you agree that satsurizumab MOA benefits the type 1 patients more than type 4 and 3? This is, you know, the question.

Well, I know there's been some academics saying that, and I know that some of them are very good academics, but they're actually incorrect because we already have data. So the theory would be that in type 1 patients who are deficient in collagen, we don't have abnormal collagen. Therefore, if we just make more bone, it'll be okay. And then type 3 and 4 have abnormal collagen, therefore it's not improved, but that's not actually what we saw. We see both of them have improved reduction of fractures, and in fact, The ones fractured we did see were in type 1 patients, I think, were some of the ones not in type 3 to 4. So the truth is all of them are improved because while one's a deficient collagen and one is abnormal collagen, whether deficient or abnormal, the net benefit of making more bone is greater bone strength and reduced fractures. So it actually works in all three. And the historical clinical view of why is going to change because the truth is that even with abnormal collagen, The bones can be strengthened, we believe, in these patients, and that's what we've seen, and that's in the data from phase two. And so we're confident that the type will not matter. You get the same bone marrow density effect, and the strength improvement will be the same, regardless of the collagen mutation.

Thank you very much.

Our next question is from Maury Raycroft with Jefferies.

Hi, congrats on the progress and thanks for taking my question. I'll ask one on OI as well. Just I guess based on what you know about the baseline characteristics and expectations for variation, can you provide any perspective on how you're thinking about the range of effect sizes on AFR reduction that would be needed to succeed on the second interim?

Yes. We've had that question in various forms of it, like what's clinically meaningful for actual reduction? I think for clinically meaningful, most people say at least 30%, 40% would be clinically meaningful. Bisphosphates are probably 20% or less, so anything like 30%, 40% or better. We don't have a sense now for sure what the power would tell us. As I said before, when the curves separate, they're linear essentially, and so we saw them separate within two to three months of treatment, which means when they get to even just, you know, 9, 10% improvement in bromel density, there's already a separation in fracture frequency. But after that, though, it appears relatively linear, which tells me then that the percent reduction on the slopes won't really change that much over time. And therefore, I don't think you can think about, like, when you hit will determine what percent reduction you get. I think you have to think of it more as, A slope and the time will just depend how far apart the two lines are, how many fractures accumulated in one arm versus the other to give you the power. Does that answer your question?

Yeah, I think so. It's a helpful perspective. Thank you.

Our next question is from Laurie Chico with Wedbush.

Hi, thank you very much for taking the question. This is Dylan on for Laurie Chico. So, for Chris Vita, could you expand further on key growth drivers in the quarter, and maybe what is helping drive uptake more specifically in the Latin and Turkey regions, or I guess what is unique about patient identification efforts in these regions?

Okay. Well, Chris Vita is growing really well in Latin America, but I think it's growing recognition of how much patients do. I don't know, Eric, have you had any thoughts on what you say about how white is growing in Latin America particularly well?

Yes, as I had stated in the opening remarks, that patients are having a good experience with the product, and physicians are now treating more and more of their patients to include adult patients in the LATAM region as well.

It's a little bit about word of mouth and propagation of that. We don't have a particularly prominent patient diagnosis function in Latin America. There are certain doctors, I mean, employees that are doing patients fine, but it's not quite the same because we don't have the same tools in South America that we have in the U.S. We don't have the codes, nine codes, ten codes, and other things to help us. It's a little bit more word of mouth, but I think It's impressive, but I believe the sound feeling of doctors that this is transformative for patients means they're just there. They want to get more and more on. When I went down to the meeting last year, the Latin American, the bazillion meeting on these patients, it was clear difference from the very first meeting we did at launch that every doctor had a story of how their kids were doing and were grateful and excited about it and were happy to be able to do something for these kids. So I think that mood is good. And the fact we're getting adults on is great, too, because we certainly had gotten primarily peds on originally.

Yeah, so in addition to the strong demand for both pediatric patients and adult patients, as I stated, we now have reimbursement with the national authorities. Yeah, in Brazil. Brazil as well as Mexico.

Yeah, that's what's really driven it for Brazil and Mexico, driven a lot of the increase in uptake rather than just name patient approach. In Turkey, it's still under named patient, but the same thing's happening. Once the doctor starts treating people to see what happened, you know, over a period of a year, they see how their bones are doing, how the kids are doing, they get adamant about getting more kids on, and parents or friends of people find out, and that's what a good drug will do. Even in a named patient setting, people hear about a story, and they all want to get something for their kids. So we're excited about that continued growth of the product internationally, and we're I think the investment in Latin America and the top tier team in Turkey have been rewarded by being able to build a really solid brewing business for the company.

And I think that just sets us up well for when we bring CitrusMap to the marketplace.

It will, because I think there's a lot to OI everywhere as well. Thank you for the question.

Our next question is from Jack Allen with Baird.

Great. Thanks for taking the questions, and congratulations on the progress made over the course of the quarter. One more logistical one on citruzumab. Have you pointed investors towards how many of the patients had 12 months of data at that first interim readout? It sounds like it was the minority of patients, but I'd love to hear if you're willing to put a little bit more finer point on the percentage of patients. And then also on citruzumab, I wanted to ask you about any disclosures you've made on the impact that citrusumab has had on bone pain. We recently did a call with a physician who mentioned bone pain is a key symptom for these OI patients, and I'd love to hear any impacts citrusumab could have there. Thank you.

Okay. I'll talk a little about the IE1, and then maybe you can touch on the repression scale scores, or just a little bit about the pain, I guess. So, as the Just to understand the enrollment curve, we had a lot of patients enroll in the last two to three months of that trial, right? It was very much a hockey stick. So when we had the minimum was seven months at that time point, we had a lot of people who were at eight, nine, 10 months, right? And a relatively smaller number at the 12 to 17 month timeframe, relatively smaller tail, right? So the majority of patients had less than a year at that time. In order to get the majority to have a year, you would take another two months or three months from when the cut was made. Does that make sense? So it's a very steep accumulation at the end. A lot of the patients were less than a year then. The majority were less than a year at the first interim. So it will be a significant difference in the number of patients that have, let's say, exposure beyond the two to three month period where they get the bone effect. So let's talk about something other than fraction. I think it's actually really important, it's true for Crescita too, that things other than the bones often are drivers. What's our thought from what we've seen in the Phase II data, Aaron?

Yeah, no, agree. Pain is a big part of this and certainly very important to patients and an important part of the evaluation for the clinical trial. So we are focused on pain, comfort, subscales, and really focusing more on type of assessments that you would do with sports physical functioning. We are also doing a traditional SF-36 to look at this, but that's definitely following pain over the long term. In phase two, we did hear a lot of improvement there. Anecdotally, we have heard that patients have had a lot of improvement in pain scores.

Yeah, I would say, too, based on how kids were feeling, like they're running, hey, I want to go do sports and stuff, they were feeling different, too. I mean, whether it's pain or fatigue or generally, you know, malaise, basically patients also got pretty energized, I think, right? And so that's also what happened with Christina, by the way. It's why Christina's pick up was so fast because kids feel good, parents see it. And I think that's happening with OI too. I think when your bones get stronger, even a little bit stronger, your body feels it and you know it. So we're excited about it. When we look at how many patients we have for that program and the fact that it's more than even with XLH, it's pretty clear that this program should exceed what we've done with CRISFIDA, and I think we'll launch more rapidly. We just, of course, have to get our IE2 or our final data in hand and get to a file, but we're excited about the opportunity being larger than it is even with CRISFIDA. There are very few times you get to do something amazing like that again, and we're really thankful to have an opportunity to take on a bone disease like osteogenesis imperfecta and turn it around for patients in the future. Thank you for the question.

Thank you. There are no further questions at this time. I'd like to hand the floor back over to Joshua Higa for any closing comments.

Thank you. This concludes today's call. If there are additional questions, please contact us by phone or at irultragenics.com. Thank you for joining us.

You may disconnect your lines at this time. Thank you for your participation.