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

Good afternoon, and welcome to the Ultragenyx First Quarter 2025 Financial Results Conference Call. [Operator Instructions] 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 ultragenyx.com. Joining me on this call are Emil Kakkis, Chief Executive Officer and President; Erik Harris, Chief Commercial Officer; Howard Horn, Chief Financial Officer; and Eric Crombez, 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 a 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 in osteogenesis imperfecta, patients in the Phase III studies 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 GTX-102 in 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 in 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 in Wilson disease, the study is now enrolling the fourth dose-finding cohort 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 the second to be submitted. The DTX401 for GSDIa BLA submission is on track for mid-2025 after successfully completing the PPQ runs, the qualification last essentially at our manufacturing facility in Bedford, Massachusetts. The UX111 for Sanfilippo 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 regulatory 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 time line. 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 PDUFA 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 U.S. BLA 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. Erik, 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 Crysvita 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 Crysvita. 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, Kyowa Kirin, is leading commercialization for Crysvita. 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 -- it is fulfilling to see that adults around -- adults have exceeded the make up more than half of patients on therapy, considering the skepticism around adult demand at launch. We expect 2025 U.S. Crysvita revenue to continue growing as they work to identify new pediatric and adult patients with XLH and convert them to treatment. Moving on to Dojolvi 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 Dojolvi 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 Evkeeza, which we began commercializing in our territories outside of the U.S. in 2023. In the EMEA region, we have patients on reimbursed therapy for 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 named 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 Evkeeza 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 Crysvita in 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, Erik, 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. Crysvita 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 Dojolvi. It contributed $17 million, consistent with its expected steady growth trajectory. Evkeeza contributed $11 million as demand continues to build following launches in our territories outside of the United States. And Mepsevii 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 noncash 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 2 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 Evkeeza 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 3 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 GAAP 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 million 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 Evkeeza in Europe and Japan. Crysvita revenue is expected to be between $460 million and $480 million, which includes all regions and all forms of Crysvita revenue to Ultragenyx. This range represents 12% to 17% growth over 2024. Dojolvi revenue is expected to be between $90 million and $100 million, which represents 2% to 14% growth over 2024. As in prior years, our Dojolvi 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 Crysvita. With that, I'll turn the call to our CMO, Eric Crombez, 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 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 midyear 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 (sic) [ GTX-102 ] for the treatment of Angelman syndrome. We have set an ambitious goal of enrolling a 120-patient pivotal study in less than 1 year. I'm proud to report that we are on track to achieve this goal, and we are actively working with sites in the U.S., 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, DTX401 for the treatment of Glycogen Storage Disease e Type Ia. In our press release today, we shared some of the additional crossover data that will be included in our BLA filing midyear. During the crossover period, patients demonstrated even greater reductions in total daily cornstarch at their last visit compared to baseline in both the ongoing DTX401 group and the placebo crossover to DTX401 group. Patients in the DTX401 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 DTX401 group demonstrated a similar 64% reduction in daily cornstarch at their last visit, where the mean duration on therapy with DTX401 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. DTX401 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 midyear. 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 2 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 discontinuation 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 arm. 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 osteogenesis imperfecta studies have now enrolled for at least 12 months, 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 of patients in the Phase II portion of the Orbit study gives us confidence the treatment effect with setrusumab in osteogenesis imperfecta is transformative for these patients. In closing, we expect 2025 to be the most productive year in our company's history and multiple Phase III studies enrolling or reading out data, we are in a 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.

[Operator Instructions] Our first question is from Yaron Werber with TD Cowen.

Great. Not surprisingly, it's going to be about setrusumab, 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 6 to 7 months. Can you give us a sense kind of what it was seen when it was at 14 months, the latest cut that was at ASBMR?

Sure, Yaron. Thank you. So I don't know if I actually use the word dispersion because that's like a statistician term. I usually mentioned 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 fracture rate greater than three and some less. And we stratified in the trials that those with greater than three would be stratified equally between the treatment and placebo group as with 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-value. 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 co-variable, meaning we'll help correct for that in the way we analyze it. which help assure that 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 IA2. We think we have a good shot of hitting IA2 based on everything we know. But we are very strongly positive on the trial, whether IA2 or the end is going to be successful. So let's talk about the fracture reduction. We announced Phase II data after 6 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. You might be wondering, well, how is the number the same? I would look at this is 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, right? So the two lines are running apart from each other. If you cut those -- the two lines earlier, they're not as far apart. But if you wait for those 2 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 would 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 suggests that we could hit it i.e. two, it's a reasonable shot. Now we are -- we did do an analysis of our Phase II data for those that have heard this from me. We did take the same data to analyze the patients as if their prior year was on 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 statistical version of it, we could go into. But 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 IA2 or at the end. All right. Let's go on.

Our next question is from Tazeen Ahmad with Bank of America.

Emil, I also have a question on OI. But 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?

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 us is variation, variability in patients. But based on the profound difference in bone mineral density change that we see that happens within 2 to 3 months and the fracture rate effect happens within 2 to 3 months, we feel pretty good about IA2 hitting, but confident about overall the study hitting even at the end, if not at the IA2. So I can't tell you a reason why, but variation is always the thing that can create complexities. But given that the patients -- the program is 159 patients, that's a pretty large study. And we were -- the data we're talking about before was 24. So I think we've got a lot of power in there, but -- and 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 Gena Wang with Barclays.

Maybe switch gear a little the nonfundamental questions. I think it was the recent CBER nomination of Vinay Prasad. And I think there is a lot of uncertainties. We saw massive sell-off in the biotech sector. And so Emil, maybe wanted to get your thoughts like where do you see that could be potential impact to -- specifically in the rare disease space? And how do you deal with or what will be the strategy you have dealing with this situation? I know there are 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 has a baseline bisphosphonate. And then the washout period in the late enrollment period, you did skip the washout period. So would that be any concern regarding, say, the placebo fracture rate picking up at some point? Would that have a delay rather than, say, 12 months or they need a little bit longer time so that we can see the placebo arm, the fracture rate start to pick up?

Very good. So yes, the CBER appointment, we don't think it was a good choice of 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 Makary has been talking about the importance of rare disease approvals and thinking how to improve and accelerate the process and reduce the time of development. So we'll have to anchor to that discussion and point he's made and see what Prasad does. I think for our own program, for UX111, we have lots of clinical data in the program. I'm less concerned about it because of the 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'd be important for accelerated approval to be available for a lot of the gene or cell therapies. And it would be important to make carry's public commitment to try to move these things forward. It's something that he follows through on. How Prasad will do that, we don't know. But I think the FDA is very important. The industry supports FDA in their mission, and we just hope that they continue to make good decisions. On the second question, so more than 80%, 89% or something like that were on bisphosphonates in the study, right, Eric?

Right.

And the washout time frame is in the 1- to 2-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 mineral densities decline. But we don't think that effect is really a meaningful effect compared to the dramatic effect on bone mineral density that's going to happen with setrusumab, right, where for the 5 to 12 group, we had a 29% increase. The bone mineral density improvement just -- 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 bisphosphonates effect over the period. But remember, setrusumab arm will also have some antiresorptive 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.

Our next question is from Salveen Richter with Goldman Sachs.

This is [ Lydia ] on for Salveen. Congrats on all the progress. Just maybe another one on setrusumab. 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?

Yes. So when we -- the DMC has 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. So 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 said what all the data might be in or not in that release. But different from interim one, we are having to fully clean the database for a potential filing from that data set. So the time to data would be faster than we had said for the IA1 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 IA2 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.

Our next question is from Anupam Rama with JPMorgan.

This is actually Malcolm Kuno on for Anupam. So where are you on your enrollment curve for the Angelman program? And have you opened all of the global sites for the program yet?

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

Yes. So like we said, our plan is to fully enroll that study this year. We are committed to that. We have really prioritized that and leverage the experience we had with OI and really enrolling 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.

Our next question is from Kristen Kluska with Cantor.

You talked about potential variation factors. I wanted to see any 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 a 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 question. 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. Yes.

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?

We haven't said. It depends. They are 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 Yigal Nochomovitz with Citi.

Have you commented at all on the distribution of the types for OI for 1, 3 and 4 for the Phase II 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 in on the second interim, is that a fail or a win? It's -- I mean, I would -- I think I know, but I'm not sure actually. So I was 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.

So on the OI types, I think we've disclosed before that in the Phase II study, there were 7 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 and about half the patients are type 3 and 4 approximately there in the study. So it's definitely an increase in Type 3s and 4s in the Phase III study than they were in the Phase II study, all right? Now for tolerance, we haven't set that like how many sigfigs 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 I would probably -- 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 was an issue. But -- so that's the basic -- the tolerance question. And then the last one was whether there was a p-value and the others, 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 it was -- study was continuing and no result. So what we know from the prior analysis of Phase II though, that the p-value was 0.014 at 14 months. So we think there's a reasonable chance of hitting IA2, a pretty good chance of hitting IA2 and a much better chance of hitting IA2 at the 0.01 threshold than there was at IA1 with 0.001.

Our next question is from Joseph Schwartz with Leerink.

This is Will on for Joe. Congrats on the progress this quarter. So one for us on Angelman. Now with three ASOs that are in or nearing pivotal development, including the one from Roche that was recently revived, how 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, Will. We are not -- usually combi working in competitive space with a lot of products in the same space. So this will be a new thing. Usually, we're working on first-ever treatments by ourselves. So it's definitely a different space. I would say in the regard to 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 Ionis molecule. The Roche molecule is sort of coming back into development. I am not concerned about. I think that, that drug is even less potent and has other questions marks. 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, we have almost 70 patients on drug that we're going to have a pretty big body of kids who have been on drug several years. I think how those kids are going to be 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. And we know 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 -- three 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 Angelman.

Our next question is from Liisa Bayko with Evercore ISI.

I just wanted to clarify, sorry to ask many questions on just setrusumab. 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 a follow-up on an earlier question. If the data reads out 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?

Yes. So on the timing of data because I think people -- some people have had an unrealistic expectation that you would clean, lock and analyze the data in a couple of weeks or something. But this is an international Phase III study, and this clean and walk 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 filing. So -- there is -- normally, it takes a Phase III around 8 weeks of an international study to clean and lock the database, plus there will be some time to analyze and have a DMC meet and disclose. So at the time we find the result, we will -- there'll 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'd be an initial read and some further. So we're going to leave that open right now. But our expectation is that we'll be -- 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, Liisa, how it's going to flow.

Okay. What -- so what -- I understand what took the IA1 a little bit longer, just to understand the differences there. That's my final question.

Yes. What happened in 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 of months. In other words, if I want hit, we say, oh, we're far enough along. And so we would then continue collecting data for a couple of 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 2 months, but probably 3 to 4 months because we have to clean and lock it. So the time frame here is much faster because we're going to clean the whole database this time, and we would be able to release top line data sooner than we would have at IA1.

Our next question is from Luca Issi with RBC Capital.

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 miss 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 the second interim look, given my understanding is that you need to get approved by the end of 2026 in order to get the PRV given that there's sunsetting that program. Any context there, much appreciated.

Yes. 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 P values. We won't know if it's closed. We do have PI designation, and we'd have to get approved by October. So whatever time frame we file would have to be within the time frame to get approval by October. Obviously, by IA2, 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 to, 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 Sanfilippo and if the DTX104 gets approved for GSDIa. 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 become up.

To clarify that the...

The 143 PRV is in October of 2026. We need approval by October 2026.

Our next question is from Joon Lee with Truist Securities.

This is Mahdi on for Joon. So I go on OI and follow up Yigal's question on composition of OI types. So do you agree that setrusumab's MOA benefits the type 1 patients more than Type 4 and 3. This is the question.

Well, I know there's been some academics saying that, but -- and I know some of them very good academics, but they're actually incorrect because we already have data. So it's not -- the theory would be that in type 1 patients have deficient collagen, don't have abnormal collagen. Therefore, if we just make more bone, it will be okay. And the type 3s and 4s have abnormal collagen, therefore, it's not improved, but that's not actually what we saw. We see both of them have improved reduction in fractures. And in fact, the ones fractures we did see were in type 1 patients, I think were some of the ones not type 3s and 4s. So the truth is all of them are improved because while one is a deficiency collagen and one is abnormal collagen, whether deficient or abnormal, the net benefit of making more bone is bone, greater bone strength and reduced fractures. So it actually works in all three. And historical clinical view of OI 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 II. And so we're confident that the type will not matter. You get the same bone mineral density effect and the strength improvement will be the same regardless of the collagen mutation.

Our next question is from Maury Raycroft with Jefferies.

Congrats on the progress. 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. So we've had that question in various forms of it, like what's clinically meaningful fracture reduction. I think for clinically meaningful, most people say at least 30%, 40% would be clinically meaningful. Bisphosphonates 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 2 to 3 months of treatment, which means when they get to even just 9%, 10% improvement in bone density, there's already a separation in fracture frequency. But after that, 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 is -- 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?

Yes. Yes, I think so. That's helpful.

Our next question is from Laura Chico with Wedbush.

This is Dylan on for Laura Chico. So for Crysvita, could you expand further on key growth drivers in the quarter? And maybe what is helping drive uptake more specifically in the LatAm and Turkey regions? Or I guess what is unique about patient identification efforts in these regions?

Okay. Well, look, Crysvita is growing really well in Latin America, but I think it's growing recognition of how much patients do. But I don't know, Erik, if you had any thoughts on what you say about how why it's growing in Latin America, particularly well?

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.

So it's a little bit about word of mouth and propagation of that to the -- we don't have a particularly prominent patient diagnosis function in Latin America. There are certain doctors -- I mean, employees that are doing patient 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. like we don't have the codes, 9 codes, 10 codes and other things to help us. But yes, so 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. It means they're just -- they're -- they want to get more and more on. When I went down to the meeting last year, the Latin Brazilian meeting on these patients, it was a clear difference from the very first meeting we did at launch that every doctor had a story of how their kids were doing, and we're grateful and excited about it, and we're 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. So...

Yes. 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...

In Brazil.

Brazil as well as Mexico.

Yes, that's what's really driven for Brazil and Mexico, driven a lot of the increase in uptake rather than just named patient approach. In Turkey, it's still under named patient. But the same thing is happening. Once the doctor starts treating people to see what's happening over a period of the year, they see other bones doing, other 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 an inpatient 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 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 growing business for the company.

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

It will because I think there's a lot to OI everywhere as well.

Our next question is from Jack Allen with Baird.

Congratulations on the progress made over the course of the quarter. One more logistical one on setrusumab. 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 setrusumab, I wanted to ask you about any disclosures you've made on the impact that setrusumab 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 impact setrusumab could have there.

Okay. I'll talk a little about the IA1 and then maybe you can touch on the impression scale scores or give us a little bit about pain, I guess. So just to understand the enrollment curve, we had a lot of patients enrolled in the last 2 to 3 months of that trial, right? It was very much a hockey stick. So when we had -- the minimum was 7 months at that time point, we had a lot of people who were at 8, 9, 10 months, right, and a relatively smaller number at the 12- to 17-month time frame, relatively smaller tail, right? So the vast 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 2 months or 3 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 2- to 3-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 Crysvita, too, that things other than the bones often are drivers. What's our thought from what we've seen in the Phase II data, Eric?

Yes. No, I 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 definitely following pain over the long term. In Phase II, we did hear a lot of improvement there. Anecdotally, we have heard that patients have had a lot of improvement in pain scores.

Yes. I would say to you based on how kids are feeling like they're running -- hey, I want to go to sports and stuff, they were feeling different, too. I mean whether it's pain or fatigue or generally malaise, these two patients also got pretty energized, I think, right? And so that's also what happened with Crysvita, by the way. It's why Crysvita the pickup was so fast. kids feel good, parents see it. And I think that's happening with OI 2. 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 Crysvita, and I think we'll launch more rapidly. We just, of course, have to get our IA2 or final data in hand and get to a file. But we're excited about the opportunity being larger than it is even with Crysvita. There's very few times to 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. 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 [email protected]. Thank you for joining us.

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