Ultragenyx Pharmaceutical - Earnings Call - Q1 2025

Executive Summary

• Q1 2025 revenue was $139.3M, up 28% year over year; EPS was ($1.57), an improvement from ($2.03) in Q1 2024. Segment detail: Crysvita $102.9M (+25% YoY), Dojolvi $17.0M, Evkeeza $11.0M, Mepsevii $8.4M.
• Versus S&P Global consensus, revenue missed ($139.3M vs $144.5M*), while EPS beat (($1.57) vs ($1.65)). EBITDA also beat (actual ($133.9M) vs consensus ($139.0M)). Values marked with * retrieved from S&P Global.
• Full-year 2025 guidance reaffirmed: total revenue $640–$670M; Crysvita $460–$480M; Dojolvi $90–$100M; expected 14–20% YoY revenue growth and reduced operating cash burn versus 2024.
• Near-term catalysts include UX111 priority review with PDUFA on Aug 18, 2025 and UX143 (setrusumab) Phase 3 Orbit/Cosmic interim analyses in mid-2025, both cited as on track by management.

What Went Well and What Went Wrong

What Went Well

• Strong commercial execution: Crysvita revenue rose 25% YoY to $102.9M, with Latin America & Türkiye product sales up 52% YoY to $55.1M; Evkeeza reached $11.0M as launches outside the U.S. progressed.
• Guidance confidence and cash runway: FY25 revenue guidance reaffirmed and management expects reduced net cash used in operations in 2025; quarter-end cash, equivalents, and marketable debt securities were $563.0M.
• Pipeline momentum: UX111 BLA mid-cycle review completed; inspections underway; UX143 databases being cleaned for IA2; DTX401 BLA filing targeted mid-2025 after successful PPQ runs.

What Went Wrong

• Top-line miss vs consensus: Q1 revenue of $139.3M missed S&P Global consensus ($144.5M*), driven in part by uneven ordering patterns (management cautions on LatAm variability). Values marked with * retrieved from S&P Global.
• Operating intensity still high: Total operating expenses were $282.2M, up vs Q3 2024 and only modestly lower than Q4 2024; operating loss was ($142.9M).
• Net cash used in operations was $166M for Q1 (seasonally higher due to bonuses and milestone payments), underscoring continued cash consumption prior to anticipated pipeline inflections.

Transcript

Operator (participant)

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.

Joshua Higa (VP 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, Eric 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.

Emil Kakkis (CEO and President)

Thanks, Josh, and good afternoon, everyone. In the first quarter, we continue 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 U.S. 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 imperfecta, patients in the phase 3 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 and Angelman syndrome, the phase 3 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 3 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 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 a second to be submitted. The DTX401 for GSD1A BLA submission is on track for mid-2025 after successfully completing the PPQ runs, the qualification lots, 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 remains on track. Last month, we had our mid-cycle review meeting that occurred on the standard timeline. We also know that inspections of the manufacturing facilities and clinical sites have been scheduled according to the 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 UX111 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. Eric, I'll hand it off to you to go through the commercial team's execution in the first quarter.

Eric Harris (CCO)

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 adult demand it is fulfilling to see that adults around adults have exceeded the.

Emil Kakkis (CEO and President)

Make it more than half.

Eric Harris (CCO)

Make it 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% teens 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 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 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 Latin America, 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.

Howard Horn (CFO)

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. 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. 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 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 3 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 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 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-$670 million, which represents 14%-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%-17% growth over 2024. Dojolvi revenue is expected to be between $90 million and $100 million, which represents 2%-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 named 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.

Eric Crombez (CMO)

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 3 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 2. Based on the phase 2 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-102 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 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 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 corn starch 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 corn starch 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 corn starch observed at week 48.

Patients in the placebo to DTX401 group demonstrated a similar 64% reduction in daily corn starch 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 corn starch 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 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 40/13. 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 two 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 two 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 % 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 been 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 two portion of the Orbit study gives us confidence that the treatment effect with rituximab and osteogenesis imperfecta 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 million-$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.

Operator (participant)

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 that participants limit themselves to one question and one follow-up and re-enter the queue for additional questions. One moment, please, while we pull for questions. Our first question is from Yaron Werber with TD Cowen.

Yaron Werber (Managing Director and Senior Biotechnology Research Analyst)

Great. Thank you so much for taking my question. You know, not surprisingly, it's going to be about rituximab, 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 two, the dispersion is not really shown. We can tell that there's variability in how many fractures patients have at baseline. Can you maybe explain to us what you mean by dispersion, maybe why it's important? 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 seeing when he was at 14 months, the latest cut that was at ASBMR? Thank you.

Emil Kakkis (CEO and President)

Here around, 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. We know we have people who can have more than three fractures a year or a fracture rate of greater than three and some less. What we stratified in the trials is that those with a greater than three would be stratified equally between the treatment and placebo group, as would the ones below that. How it's distributed can have some impact on the probability of success just because variation is what really affects p-value. 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 helps assure that it doesn't have a substantial impact. We're also stratifying by age in the trial. 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. 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 at IA2 or the end, it's going to be successful. 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. You might be wondering, how come the number is the same? I would look at this as think of it as a line of accumulated fractures. The accumulated fractures in one group are going up at a steep rate, and the slope of the other line is only 67% less, right? The two lines are running apart from each other. If you cut the two lines earlier, they are not as far apart, but if you wait for those two lines to progress further, they are further apart.

The slopes are still 67%, the same treatment effect size, but the p-value is better. What's happening at interim one is that they may not have separated far enough yet, and it would only have happened if we had a lot of fractures. By the second time, we'll have run longer that we should have much better separation. From that analysis, it suggests that we could hit at IA2. It's a reasonable shot. Now, we did do an analysis of our phase two 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 placebo and compared to their current year on treatment. With the negative binomial, you get the same mid-60% kind of reduction, and all right, with a good p-value.

Just to be clear, if you do it by the method we're using in phase three, you get a very similar result. Just simply wondered whether the different statistical approach would matter. Variability is an issue. Dispersion or the 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.

Operator (participant)

Our next question is from Tazeen Ahmad with BofA Securities.

Tazeen Ahmad (Managing Director in Equity Research)

Hi, good afternoon. Thanks for taking my question. 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. 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.

Emil Kakkis (CEO and President)

Right. It will not be the next assessment; it is the final assessment for the study, and that p-value threshold will be 0.04. It would be a lot easier to hit 0.04. We think that we will hit one or the other based on our experience, what we have seen. I do not think we could miss the 0.04 at that point with 18 months of time. As always in rare disease programs, the thing you always are battling against is variation, variability in patients. Based on the profound difference in bone mineral 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 IA2 hitting, but confident about overall the study hitting even at the end, if not at the IA2.

I cannot tell you a reason why, but variation is always a thing that can create complexities. Given that the patients, the program is 159 patients, that is a pretty large study. The data we are talking about before was 24. I think we have got a lot of power in there, and we have done everything we can to manage variations. I feel good about we will hit it this year either at 0.01 or at 0.04 after 18 months.

Operator (participant)

Our next question is from Gina Wong with Barclays.

Gena Wang (Managing Director and Biotech Equity Research)

Thank you for taking my questions. Maybe a little bit switch gear, a little bit the non-fundamental questions. I think it was a recent CBAR nomination of Vinay Prasad, and I think there's lots of uncertainties. We saw massive sell-off in the biotech sector. Abby, maybe you 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 would be the strategy you have dealing with this situation? There's still open questions, a lot of uncertainties there. My second question is also go back to the OI. I think a recent discussion we had, you did mention that 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.

Would that be a concern regarding, say, the placebo fracture rate 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 arm, the fracture rate start to pick up?

Emil Kakkis (CEO and President)

Very good. Yeah, the CBR appointment, we do not 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 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. We will have to anchor to that discussion and point he has made and see what Prasad does. I think for our own program, for UX111, we have lots of clinical data in the program. I am less concerned about it because of the fact we have clinical data showing efficacy in addition to the biomarker data.

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 that McKerry's public commitment to trying to move these things forward is 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, more than 80%, maybe 80% or 90% or something like that, were on bisphosphonates in the study, right?

Howard Horn (CFO)

Correct.

Emil Kakkis (CEO and President)

Yeah. The washout timeframe is in the one to two-year period. We would expect the placebo patients to have steadily declining bisphosphonate effect and therefore a steadily potentially increasing fracture rate as their bone mineral densities decline. We do not think that effect is really a meaningful effect compared to the dramatic effect on bone mineral density that is going to happen with setrusumab, right? For the 5-12 group, we had a 29% increase. The bone mineral density improvement, the effect on the other groups will not be nearly so large. What it would do is both groups would have a loss of bisphosphonate effect over the period. Remember, the setrusumab arm will also have some anti-resorptive effect from the drug itself.

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, you think?

Howard Horn (CFO)

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. In any sense, that could be considered an upside.

Emil Kakkis (CEO and President)

Yep. Very good. Thank you.

Operator (participant)

Our next question is from Salveen Richter with Goldman Sachs.

Lydia Erdman (Biotech Equity Research Analyst)

Hi, this is Lydia for Salveen. Thanks so much for taking our questions and 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? Thanks so much.

Emil Kakkis (CEO and President)

Yes. When the DNC has presented the information on Orbit, if it is positive, they will 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 will also inform the street that the study is continuing to the end. If you have not heard from us because the decision has not happened yet, a decision either is moving forward to the final assessment or it is ending at the interim will be clear. We have not set 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 potential filing from that data set. The timed data would be faster than we have said for the IA1, where we had only partial lock and we had to continue the trial.

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 will not unblind the COSMIC data and we will wait for both studies to go to the next assessment. Okay?

Lydia Erdman (Biotech Equity Research Analyst)

Thanks so much.

Operator (participant)

Our next question is from Anupam Rama with JPMorgan Chase & Co.

Anupam Rama (Managing Director and Senior Equity Analyst)

Hi, thanks for taking the question. This is actually Malcolm Kuno on for Anupam. Where are you on your enrollment curve for the Angelman program, and have you opened all of the global sites for the program yet?

Emil Kakkis (CEO and President)

I'll ask Eric to comment on that.

Eric Harris (CCO)

Yeah. Like we've said, 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 for us for rare disease, a relatively large pivotal trial. We certainly want to do this as quickly as possible. Yes, our global sites are active and beginning to screen those patients.

Emil Kakkis (CEO and President)

All sites active.

Anupam Rama (Managing Director and Senior Equity Analyst)

Excellent. Thank you.

Operator (participant)

Our next question is from Kristen Brianne with Cantor.

Kristen Kluska (Equity Research Analyst)

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. I know the Orbit trial has a range of about 20 years. Is there anything you're able to share?

Emil Kakkis (CEO and President)

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 questions. 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?

Eric Harris (CCO)

No, I think that covers it.

Emil Kakkis (CEO and President)

Yep.

Kristen Kluska (Equity Research Analyst)

Thanks. And then just to clarify, if IA2, 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.

Emil Kakkis (CEO and President)

Yeah, 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?

Operator (participant)

Our next question is from Yigal Dov Nochomovitz with Citigroup.

Yigal Nochomovitz (Director and Senior Biotech Analyst)

Hi, thanks. Have you commented at all on the distribution of the types for OI for one, three, and four for the phase two versus the Orbit trial? 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. 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. 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.

Emil Kakkis (CEO and President)

On the OI types, I think we've disclosed before that in the phase two study, there were seven type threes and fours and 17 type ones.

Then because the doctors were then impressed with the results, then they were interested in bringing in their more severe three and four patients. We ended up with more type threes. We thought half the patients are type three and four or approximately there in the study. It is definitely an increase in type threes and fours in the phase three study than they were in the phase two study. All right. Now, for tolerance, we have not set that like how many sig figs of significance. Honestly, I do not have an answer for you, but I would say if it was like 0.015 or 0.016, that is not less than 0.01, right?

That would probably 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 should not overreact if there was an issue. That is the basic, the tolerance question. The last one was whether it was a p-value. The others, we have not 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. What we know from the prior analysis of phase two, though, is that the p-value was 0.014 at 14 months.

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. All right. Thank you, Yigal. Thanks.

Operator (participant)

Our next question is from Joseph Schwartz with Leerink.

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

Emil Kakkis (CEO and President)

Thank you. We are not usually a company working in competitive spaces with a lot of products in the same space. This will be a new thing. Usually, we're working on first-ever treatments by ourselves. It is definitely a different space. I would say in regard to these ASOs, ultimately, the most potent and effective drug will be the one that will tend to dominate. That does not 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. I do believe our drug is the most potent and has shown that. 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. I think that that drug is even less potent and has other question marks. If there is 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 two study and we have almost 70 patients on drug, that we are going to have a pretty big body of kids that 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 three study. That will be what people want to see. What is my future like for my kid if I am on this?

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. 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. My hope going down the road is that the top three ASO treatments will be our first product, then our second improvement, and then the third next gen that comes out because we intend to be the leaders in Angelman.

Operator (participant)

Our next question is from Liisa Bayko with Evercore ISI.

Liisa Bayko (Analyst)

Hi. Thanks for taking the question. I just wanted to clarify, sorry to ask so many questions on setrusumab. Can you give us a little greater sense on where you are in terms of timing, what happens from here to data? I just wanted to 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? Thanks.

Emil Kakkis (CEO and President)

Yeah. So on the timing of data, because I think some people may have had an unrealistic expectation that you would clean, lock, and analyze the data in a couple of weeks or something. This is an international phase 3 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. Normally, it takes a phase 3, around eight weeks of international study to clean and lock a database. Plus, there would be some time to analyze and have a DMC meet and disclose. 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 have not yet precisely said whether we will disclose it together at once or whether it would be an initial read and some further. We are going to leave that open right now. 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. Hopefully, that gives you an idea, Lisa, of how it is going to flow.

Liisa Bayko (Analyst)

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.

Emil Kakkis (CEO and President)

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. We would have had to keep running the study for a couple of months. In other words, if IA1 hit it, we'd say, "Oh, we're far enough along." We would then continue collecting data for a couple of months till more than half the patients had 12 months of data. We would have started doing—and we've been doing all the final visits and cleaning and locking at that time. There would have been a delay before we clean and lock. 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.

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 IA1.

Operator (participant)

Our next question is from Luca Issi with RBC Capital Markets.

Luca Issi (Senior Biotechnology Research Analyst)

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 do not hit at the second interim look, will the DSMB share with you the p-value? Just wondering whether you have a sense of whether you missed by a narrow margin or not. Maybe related, is it fair to assume that the PRV for OI is possible only if you hit at a 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 is some study in that program. Any context there, much appreciated. Thanks so much.

Emil Kakkis (CEO and President)

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 p-values. We won't know if it's close. We do have PH 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, for 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. I would also point out to you, we do have breakthrough therapy designation for this program. I think there are reasons why we could be able to accelerate things if need be. 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 DTX401 gets approved for GSD1A. I don't think there's anyone with potentially three PRVs still in play without the reauthorization. I do believe that the bill will get reauthorized. I think we've had assurances that is true, but I think right now there are so many other matters that are top of mind in Capitol Hill that that one will take a little while before it'll come up.

Luca Issi (Senior Biotechnology Research Analyst)

To clarify the.

Emil Kakkis (CEO and President)

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

Luca Issi (Senior Biotechnology Research Analyst)

Next question. Thanks, operator.

Operator (participant)

Our next question is from Joon Lee with Truist Securities.

Joon Lee (Managing Director and Biotech Analyst)

Hello. Good afternoon, and thanks for taking our question. This is Mary on for June. I go on OI and follow up Eagle's question on composition of OI types. Do you agree that setrusumab's MOA benefits the type one patients more than type four and three? This is the question.

Emil Kakkis (CEO and President)

I know there's been some academics saying that, and I know some of them are very good academics, but they're actually incorrect because we already have data. The theory would be that in type one patients, you're deficient in collagen, and we don't have abnormal collagen. Therefore, if we just make more bone, it'll be okay. Then type three and four have abnormal collagen. Therefore, it's not improved. That's not actually what we saw. We see both of them have reduction of fractures. In fact, the ones fractured we did see were in type one patients, I think, were some of the ones, not type threes and fours.

The truth is all of them are improved because while one's deficient in collagen and one has abnormal collagen, whether deficient or abnormal, the net benefit of making more bone is greater bone strength and reduced fractures. It actually works in all three. The 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. That's what we've seen, and that's in the data from phase two. We're confident that the type will not matter. You get the same bone density effect, and the strength improvement will be the same regardless of the collagen mutation.

Joon Lee (Managing Director and Biotech Analyst)

Thank you very much.

Operator (participant)

Our next question is from Maury Raycroft with Jefferies.

Maury Raycroft (Equity Research Analyst)

Hi. Congrats on the progress, and thanks for taking my question. I'll ask one on OI as well. 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?

Emil Kakkis (CEO and President)

Yeah. So we've had that question in various forms of it. What's clinically meaningful for 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 almost linear, essentially. We saw them separate within two to three 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. After that, it appears relatively linear, which tells me then that the % reduction on the slopes won't really change that much over time.

I don't think you can think about when you hit will determine what % 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?

Maury Raycroft (Equity Research Analyst)

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

Operator (participant)

Our next question is from Laura Chico with Wedbush.

Dylan Shindler (Senior Biotechnology Analyst)

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

Emil Kakkis (CEO and President)

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

Eric Harris (CCO)

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.

Emil Kakkis (CEO and President)

It's a little bit about word of mouth and propagation of that through the public. We do not have a particularly prominent patient diagnosis function in Latin America. There are certain doctors, I mean, employees that are doing patient find, but it's not quite the same because we do not have the same tools in South America that we have in the U.S. We do not have the codes, 9 codes, 10 codes, and other things to help us. Yeah, it's a little bit more word of mouth, but I think it's impressive. I believe the sound feeling of doctors that this is transformative for patients means they want to get more and more on.

When I went down to the meeting last year, the Latin America, the 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 were grateful and excited about it and were happy to be able to do something for these kids. I think that mood is good. The fact we're getting adults on is great too because we certainly had gotten primarily peds on originally.

Eric Harris (CCO)

Yeah. In addition to the strong demand for both pediatric patients and adult patients, as I stated there, we now have reimbursement with the national authorities.

Emil Kakkis (CEO and President)

Yeah. In Brazil.

Eric Harris (CCO)

Brazil as well as Mexico.

Emil Kakkis (CEO and President)

That is what has really driven it for Brazil and Mexico, driven a lot of the increase in uptake rather than just name patient approach. In Turkey, it is still under name patient. The same thing is happening. Once a doctor starts treating people to see what has happened, over a period of a year, they see how their bones are doing, how their kids are doing. They get adamant about getting more kids on. Parents or friends of people find out, and that is what a good drug will do. Even in a name patient setting, people hear about a story, and they all want to get something for their kids. We are excited about that continued growth of the product internationally. 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.

Eric Harris (CCO)

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

Emil Kakkis (CEO and President)

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

Operator (participant)

Our next question is from Jack Allen with Baird.

Jack Allen (Senior Research Analyst)

Great. Thanks for taking the questions, and 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. 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. Thank you.

Emil Kakkis (CEO and President)

Okay. I'll talk a little about the IA1, and then maybe you can touch on the impression scale scores or just a little bit about the pain, I guess. 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. When we had the minimum was seven 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 12-17 month timeframe, relatively smaller tail, right? 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 two or three months from when the cut was made. Does that make sense?

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. 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. Let's talk about something other than fracture. 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 two data, Aaron?

Aaron Olsen (Company Representative)

Yeah. 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. We are focused on pain, comfort, subscales, and really focusing more on the type of assessments that you would do with sports physical functioning. We are also doing a traditional SF36 to look at this, but 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.

Emil Kakkis (CEO and President)

Yeah. I think.

Eric Harris (CCO)

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 malaise, phase two patients also got pretty energized, I think, right? And that's also what happened with Crysvita, by the way. That's why Crysvita's pickup was so fast. Kids feel good. Parents see it. 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. 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. I think we'll launch more rapidly.

We just, of course, have to get our IA2 or our final data in hand and get to a file. We are excited about the opportunity being larger than it is even with Crysvita. There are very few times you get to do something amazing like that again, and we are 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.

Operator (participant)

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.

Joshua Higa (VP of Investor Relations)

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.

Operator (participant)

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