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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 osteogensis and Perfexa, patients in the Phase III studies have now been enrolled for at least a year and the process begun to clean and lock the databases for our second interim analysis. For GTX-one hundred two 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 and ornithine transcarbamylase deficiency or OTC, The Phase III study completed enrollment in the quarter is on track to readout data over the next year. The UX701 Wilson disease 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 ZTX-four zero one for GSDIa BLA submission is on track for mid-twenty twenty five after success of completing the PPQ runs the qualification launch essentially at our manufacturing facility in Bedford, Massachusetts.
13m 15s
The U. S. 111 for Sanfilippo syndrome BLA under review by the FDA 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 UX-one 11 BLA review thus far remain on track. Last month, we had our mid cycle review meeting that occurred on the standard timeline We also know that inspections of the manufacturing facilities and clinical sites have 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 but we did want to share enough detail for you to remain confident as we are that the 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 2020 will be a transformational year for Ultragenyx Eric, I'll hand it off to you to go through the commercials team's execution in the first quarter. Thank you, Emil, good afternoon, everyone. The first quarter, the commercial organization continued building on momentum that we saw at the end of twenty twenty four.
14m 27s
Starting with Crysvita in Latin America, we lead commercial operations.
14m 32s
Our team generated approximately 40 new start forms that led to approximately 40 patients on reimbursed therapy. We now have approximately seven seventy five 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, Kiowa Kirin, is leading commercialization for Crysvita. The first quarter twenty twenty five 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 [indiscernible] [indiscernible] exceeded the Make it more than half. 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.
16m 13s
Moving on to the AJOVY 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 reimburse 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 two seventy unique prescribers. For the AJOVY across the EMEA region, there are over two sixty 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 AFKEASA, 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.
17m 43s
We now have treated approximately two fifty 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 FTEs and revenue to contribute more meaningfully to total revenue as we continue to assess 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.
19m 7s
Thanks, Eric, and good afternoon, everyone.
19m 10s
I'll focus on first quarter twenty twenty five financial results and guidance for the year. Starting with revenue, In the first quarter of twenty twenty five, reported 139,000,000 representing 28% growth over the first quarter of twenty twenty four. Crysvita contributed 103,000,000 including $41,000,000 from North America dollars 55,000,000 from Latin America and Turkey and $7,000,000 from Europe. In total, this represents 25% growth over 2024.
19m 44s
If you focus on Latin America and Turkey, where we are responsible for generating sales, this represents 52% growth over 2024. Turning now to the Dejolvi, it contributed $17,000,000 consistent with its expected steady growth trajectory. If Keysa contributed 11,000,000 as demand continues to build following launches in our territories outside of The United States. And Mepsevii contributed $8,000,000 as we continue to treat patients in this ultra rare indication. Total operating expenses for the quarter were $282,000,000 which included R and D expenses of 166,000,000 SG and A expenses of $88,000,000 and cost of sales of 29,000,000 Operating expenses included non cash stock based compensation of 40,000,000 For the quarter, net loss was 151,000,000 or $1.57 per share. As of March 31, we had $563,000,000 in cash cash equivalents and marketable securities. Which reflects $45,000,000 in cash payments made for two milestones during the first quarter of twenty twenty five. That were achieved in the fourth quarter of twenty twenty four.
21m 2s
Specifically, $30,000,000 for a GTX-one hundred two Phase three study milestone and 15,000,000 for an EVKYSA sales milestone. In the first quarter of twenty twenty five, net cash used in operations was $166,000,000 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 $30,000,000 GTX-one hundred 2 development milestone payment I mentioned earlier. Net cash used in operations is expected to decrease in the remaining quarters of this year 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 $640,000,000 and $670,000,000 which represents 14% to 20% growth over 2024.
22m 14s
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 MEKKAZA in Europe and Japan. Crysvita revenue is expected to be between $460,000,000 and $480,000,000 which includes all regions and all forms of Crysvita revenue to Ultragenyx.
22m 37s
This range represents 12% to 17% growth over 2024. The JOLVI revenue is expected to be between 90,000,000 and 100,000,000 which represents two to 14% growth over 2024. As in prior years, our DeJolvi projections represent a blend of faster growth in countries where we commercialize, and lower growth in countries where we respond to name patient requests.
23m 4s
Lastly, with respect to tariffs, the landscape continues to evolve.
23m 9s
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.
23m 21s
With that, turn the call to our CMO, Eric Crombez, who will provide an update 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 DUX-one hundred forty three for the treatment of osteogenesis imperfecta, the Phase three 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 two. Based on the Phase two 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.
24m 6s
The Orbit and COSMIC studies will both have an interim analysis midyear after all patients have been on therapy for at least twelve 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 zero point zero 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 GTX101 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. 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.
25m 19s
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 reduction 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 one hundred and twenty weeks, This is a substantial and continued reduction compared to the 41% reduction in daily cornstarch observed at week forty eight. Patients in the placebo to DTX401 group demonstrated a similar 64% reduction in data cornstarch at their last visit where the mean duration on therapy with DTX401 was sixty nine weeks.
26m 13s
Patients in both groups have demonstrated statistically clinically meaningful reductions in daily cornstarch requirements demonstrating continued benefit from this gene therapy over time. CTX-four zero one also continues to demonstrate a consistent and acceptable safety profile with no new safety signals identified.
26m 32s
The manufacturing process at our Bedford, Massachusetts facility is going well, and we recently successfully completed our process performance qualification run. 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 four thousand thirty 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 fifty two 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.
28m
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, will be looking at the change in twenty four hour urinary copper from baseline to week fifty two and percent reduction in standard of care by week fifty two. I'll now turn the call back to Emil to provide some closing remarks.
28m 23s
Thank you, Eric. Over the first part of the year, we made tremendous progress executing on all fronts. Patients in both 43 for osteosimperfecta studies now been enrolled for at least twelve months this enables our teams to start the process of cleaning, locking the databases 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 of secusumab and osteogenesis imperfecta is transformative for these patients.
28m 55s
In closing, we expect 2025 to be the most productive year in our company's history with the commercial organization generating $640,000,000 to $670,000,000 in revenue and the development organization managing one BLA under review, a second to be submitted in middle middle of the year, and multiple Phase III studies enrolling or reading out data we are in prime position to lead the future. Of rare disease medicine.
29m 17s
With that, let's move on to your questions.
29m 20s
Operator, please provide the Q and A instructions.
29m 25s
Thank you. Now be conducting a question and answer session. [indiscernible] reenter the queue for additional questions. One moment please while Our first question is from Yaron Werber with TD Cowen. Great. So thank you so much for taking my question. Not surprisingly, if going to be about sitrusumab, the second interim analysis. And sort of one question in two parts. Maybe the first one, Emil, you've talked recently about the 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 sixty seven percent 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 fourteen months, the latest cut that was at ASBMR?
30m 56s
Thank you. Sure, Ron. Thank you. So I don't know if I actually use the word dispersion because that's like a statistician term. I usually mention variation but 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, I think, less fracture grade greater than three and some less. So we stratify in the trials that those with a 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 based on. Now the statistical method we're using the negative binomial, capture the AFR as a 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 doing a number of things that will help reduce variation, but there is a of variation in severity and fracture frequency and we think we've done what we can But that might be one reason why you might not hit IE2.
32m 13s
We think we have a good shot of hitting IE2 two.
32m 15s
Based on everything we know. But we are very strongly positive on trial whether it's IA two or the end is going to be successful. Let's talk about the fracture reduction We announced Phase II data after six months or so, and showed a sixty seven percent reduction with a p value 0.04. Now when we did the fourteen month cut of the same twenty four patients, we had the same sixty seven percent reduction in fracture frequency median And the p value, though, was 0.0014. You might be wondering, well, how is the number the same? The I would look at this as think of it as a line of accumulated fractures accumulated fractures in in one group is going up at a steep rate.
32m 59s
And the slope of the other line is is only 67% less right? So the two lines are running at apart from each other. If you cut those the two lines earlier, they're not as far apart. But if you wait for those two lines to progress further, they're further apart. The slopes are still 67%, the same treatment effect size, but the P value is better. So what's happening at interim one is that they may not have separated far enough yet and it would only would have happened if we had a lot of fractures. But by the second time, we'll have run longer than we should have better separation. So from that analysis, suggests that we could hit it I. Two, it's a reasonable shot. Now we did do an analysis of our Phase II data for those that have heard this from me We did take the same data and analyze the patients as if they're prior year was on placebo and compared to their current year. On treatment. And with the negative binomial, you get the same mid 60s percent kind of reduction. And 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.
34m 11s
Just simply wondered whether the different statistical approach would matter. So, variability is an issue. Dispersion or statistical version of it, could go into. But I think the key thing I would say is that we have plenty of power to succeed in the study whether it's IA2 or at the end.
34m 31s
All right, let's go on.
34m 36s
Our next question is from Tazeen Ahmad with Bank of America.
34m 42s
Hi, good afternoon.
34m 43s
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. We would agree that the drug is active. But if the study moves to the third interim, what would be a reason to be concerned that it would not work at the third interim? Thanks.
35m 15s
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.
35m 35s
I don't think we could miss the 0.04 at that point with eighteen months of time.
35m 41s
But as always in rare disease programs, the other thing you always are battling is variation. Variability in patients, But based on the 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.
36m
We feel pretty good about IE2 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 a thing that can can create complexities. But given that the patients the program is one hundred and fifty nine patients, That's a pretty large study. And we were the data we're talking about before was twenty four. So I think we've got a lot of power in there, but we've done everything we can to manage variations.
36m 29s
So I feel good about we'll hit it this year. Either at 0.01 or 0.04 after eighteen months. Our next question is from Gena Wang with Barclays.
36m 46s
Thank you for taking my questions. Maybe a little bit switch gear a little bit the non fundamental questions. I think it was a reason CBAR of Vinay Prasad. And I think there is a lot of uncertainties. We saw massive sell off in the biotech sector. And so, Abhi or Jamie, I 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? Mean there's still open questions, a lot of uncertainties there. And my second question is also go back to the OI. I think a recent discussion we had you did mention that like over maybe eighty percent of patient 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 factory picking up at some point? Would that have a delay rather than, say, twelve months? Would they need a little bit longer time so that we can see the placebo arm, the factory start to pick up.
38m 7s
Very good. So yes, the CBER appointment we don't think was a good choice as someone who has argued against accelerated approval for cancer programs or and that may be a concern.
38m 18s
I think we'd have to anchor back to the fact that the carrier has been talking about the importance of rare disease approvals and thinking how to improve and accelerate the process or reduce the time of development. So will have to anchor to that discussion and point he has made and see what Fesad does. I think for our own program, for UX-one hundred eleven, we have lots 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.
38m 49s
And so I think for us right now, we're not concerned. But think for industry at large, it'd be important for accelerated approval to be available for a lot of the gene or cell therapies.
38m 58s
And it would be important that it carries 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 and their mission and we just hope that they continue to make good decisions On the second question, so more than 80% to 90% something like that were on bisphosphonates in the study, right, Eric? Correct. Yes. And the washout timeframe is in the one to two period. So we'd expect the placebo patients to be have steadily declining [indiscernible] bisphosphonates effect and therefore steadily potentially increasing frac rate as their bone marrow densities decline. But we don't think that effect is really a meaningful effect compared to the dramatic effect on bone marrow density that's going to happen with cetuzumab, right? We're for the five to twelve group, we had a twenty nine percent increase The bone marrow density improvement, this those fact on the other groups will not be nearly so large. So what it would do is both groups would have a loss of this bisphosphonate effect over the period But remember, cetirizan arm will also have some anti resorptive effect.
40m 16s
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.
40m 25s
The longer it goes. Do you have anything else to add to that, Yifeng? Just that we didn't count on this. When we were designing the study, empowering the study, we did not account for that effect. So any any sense that could be considered an upside. Very good. Thank you.
40m 44s
Our next question is from Salveen Richter with Goldman Sachs.
40m 51s
Hi, this is Lydia on for Salveen. Thanks so much for taking our questions and congrats on all the progress.
40m 56s
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.
41m 9s
Yes. So when we D and C 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 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 you haven't heard from us because the decision hasn't happened yet, and a decision either is moving forward to the final assessment or it's ending at the interim will be clear. We haven't set what all the data that 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. So the time to data would be faster than we we have said for the IE1 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 IE2 is positive then the COSMIC study will be evaluated if orbit is negative, then we won't unblind the COSMIC data and we'll wait. For both studies to go to the next assessment.
42m 19s
Okay.
42m 22s
Thanks so much.
42m 25s
Our next question is from Anupam Rama with JPMorgan.
42m 30s
Hi, thanks for taking the question. This is actually Malcolm Kuno on for am. 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?
42m 44s
Well, I'll ask Eric to comment on that. Yes. So 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 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, global sites are active and beginning to screen in those patients. So I'll say it's active.
43m 17s
Excellent. Thank you.
43m 21s
Our next question is from Chris Kankoska with Cantor. Hi, good afternoon. You talk about potential variation factors I wanted to 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 twenty years. So is there anything you're able to share?
43m 56s
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 that study if there's any question. 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? [indiscernible] Thanks. And then just to clarify, if IA2 is if it does hit the analysis, will you also be announcing the same day whether COSMIC was successful as well or will those updates be separate? Thank you again.
44m 40s
We haven't said it depends. They're not happening happening. The reviews of both programs are 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.
44m 51s
We'd like to keep you guessing a little bit, right? Why make it too easy?
44m 57s
Our next question is from Yigal Nochomovitz with Citi.
45m 4s
Hi, thanks. Have you commented at all on the distribution of the types for OI for one, three and four?
45m 11s
For the Phase two versus the Orbit [indiscernible] And then also 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 mean, hypothetically, if it's like 0.011, in on the second interim, is that is that a fail or a win? It's I mean, I would I think I know, but I'm not sure, So I was just curious if you could clarify that level of detail and whether you ever told the P value for the first one the first interim? Thanks.
45m 47s
So, the OI types, think we've disclosed before that in the Phase two study, were seven Type 3s and 4s and 17 type 1s. And then because the doctors were then impressed with the results, then they were interested in bringing in their more severe three and four patients So we ended up with more Type 3s. We bought half the patients are Type three and four approximately there.
46m 12s
In the study. So it's definitely an increase in Type 3s and 4s in the Phase three study than they were in the Phase two study.
46m 19s
Now for tolerance, we haven't set that like how many sig figs of significance honestly, don't have an answer for you. But I would say if it's like 0.015 or 0.016, that is not less than 0.01, right? So that would 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, is why we shouldn't overreact it.
46m 44s
There's an issue. But so that's the basic the tolerance question. And then the last one was whether it was the PVAL and the others we haven't provided PVAL. We were not aware of the PVAL nor provided one. The interim, the first interim. We were just told that it was steady, it was continuing and no result. So what we know from the prior analysis of Phase two though that the P value was 0.014 at fourteen months. So we think there's a reasonable chance of hitting IE2.
47m 21s
Pretty good chance of hitting IA2. And a much better chance hitting IA2 at the 0.01 threshold than there was at IA1 with 0.01. Thank you, Gaul.
47m 32s
Thanks. Our next question is from Joseph Foote with Leerink.
47m 41s
Hey, all. This is Will on for Joe.
47m 42s
Thanks for taking our question and congrats on the progress this quarter. So one for us on Angelman. Now with three ASOs that are in or nearing pivotal development, including the one from Roche that was recently revived, Are you thinking about the evolution of this market?
47m 57s
And do you see a room for multiple treatment options? And how do you think these assets can 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.
48m 12s
You. Well, we are not usually a company 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 in our by ourselves. So it's definitely a different space I would say in the regard of these ASOs, 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, iASOs. But I do believe our drug is the most potent and has shown that and I think we've shown the best long term data, continuous improvement over long periods of time, that has been shown for the INS molecule The Roche molecule is sort of coming back into development I am not concerned about. I think that that drug is even less potent and has other questions, Mark. So if there's more than one out there, I think it will depend on efficacy. And what people can show. I do think that we have because we expanded our Phase II study and we have almost 70 patients on drug, we're going have a pretty big body of kids who have been on drug several years.
49m 23s
I think how those kids are going to doing are going to be probably even more 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, had a few words in the first year, but now she's speaking a few dozen words.
49m 46s
And has continued to gain ground over time. So I think that experience will be really important. I do think we're in the best position to be the leader in the ASO space and my hope going down the road that the top three ASO treatments will be our first product, then our second improvement and then the third next gen that comes out. And because we intend to be the leaders in arrangements Our next question is from Lisa Bayko with Evercore ISI.
50m 23s
Hi, thanks for taking the question. I just wanted to clarify, sorry to ask so many questions on just cetrusumab. Can you give us a little greater sense on where you are in terms of timing, what happens from here to data? And then I just wanted to understand follow-up on an earlier question. If the data reads a positive, do you say it's positive and take some time to analyze the data and come back to us with the data? Or is it is that all in one one press release? Thanks.
50m 52s
Yes. So on the timing of day, because I think people may some people have had an unreal expectation that you would clean, lock and analyze the data in a couple of weeks or something. But this is a international Phase III 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 filing. So there's normally takes a Phase III 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.
51m 28s
Disclose. So, at the time we find the result, we will there'll be a much shorter time than we had before in terms seeing what the data are. We haven't yet precisely said whether we'll disclose it together at once.
51m 43s
Or whether it'd be an initial read and some further. So we're going leave that open right now. But our expectation is that we'll be it'll be sooner to getting the top line data than it would have been in IA1 where we had some other questions.
51m 57s
So hopefully that gives you an idea, Elyse, of how it's going to flow.
52m 2s
Okay.
52m 4s
So what I don't understand what took the IA-one a little bit longer just to understand the differences there. That's my final question. Thank you.
52m 11s
Yes. What happened to IE1 is that even if the interim was positive, regulatory authorities wanted to have the majority of patients have at least twelve months of data.
52m 22s
So we would have had to keep running the study for a couple months In other words, if I want to hit, we'd say, oh, we're far enough along. And so we would then continue collecting data a couple of months till all till more than half the patients had twelve months of data. And then we would have started and we've been doing all the final visits and cleaning, walking at that time. So there had been a delay before we clean and lock So you wouldn't be able to see the data for not just two months, but probably three to four months because we have to clean and lock it. So the timeframe here is a much because we're going to clean lock the whole database this time.
52m 59s
And we would be able to release top line data sooner than we would have at IA1.
53m 8s
Our next question is from Luca Issy with RBC Capital. Great. Thanks so much for taking my question. Congrats on the progress. Just one more on Oai just to be super, super clear.
53m 20s
In a scenario where you actually don't hit at the second interim look, will the DSMB share with you the P value? Just wondering whether you will have a sense of whether you missed by a narrow margin or not. 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 that you need to get approved by the end of twenty twenty six in order to get the PRV given that they're sunsetting that program. Any context there? Much appreciate. Thanks so much.
53m 53s
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 T values. We won't know if it's close. We do have PIAG 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, I2, 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 you, we do have breakthrough therapy designation for this program. So I think there are reasons why we could be able to to accelerate things if need be. But our goal would be to get this filed in time to get a third PRB Short of that, we certainly have already potentially two PRBs in place if if 111 gets approved. For Sanfilippo and if DGX-four zero one gets approved for GSDIa. So don't think there's anyone with potentially three PRVs still in play without the reauthorization. I do believe the bill will get reauthorized think we have had the assurance of that is true, but I think right now there is some of the other matters that are top of mind in Capitol Hill that that one will take a little while before it will become up.
55m 9s
And to clarify the the 143 PRV is in October of twenty twenty six.
55m 17s
We need approval by October 2026.
55m 19s
Right.
55m 20s
Next question. Thanks, operator. Our next question is from Joon Lee with Truist Securities.
55m 28s
Hello.
55m 28s
Good afternoon and thanks for taking our question. This is Mehdi on for June. So I I go on live and follow-up Ichal's question on composition of OI types. So do you agree that sacituzumab MOA benefits the Type one patients more than Type four and three This is the question.
55m 57s
Well, I know there's been some academics saying that, but and I know that some of them are very good academics, but they're actually incorrect. Because we already have data. So it's not the theory would be that in Type one patients here deficient in collagen, we have abnormal Therefore, if we just make more bone, it'll be okay. And the Type three and four have abnormal collagen, therefore it's not improved, but that's not actually what we saw We see both of them have improved reduction of fractures And in fact, the ones fractures we did see were in type one patients, think were some of the ones not type three to four. So the truth is all of them are improved because while one is a deficiency of collagen and one is abnormal collagen, whether deficient or abnormal, the net benefit of making more bone is greater bone strength and reduced fractures.
56m 46s
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 density effect the strength of brim will be the same regardless of the collagen mutation.
57m 15s
Thank you very much.
57m 20s
Our next question is from Maury Raycroft with Jefferies.
57m 26s
Hi, congrats on the progress and thanks for taking my question. I'll ask one on OI as well. Just 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 reduction would be needed to succeed on the second interim?
57m 48s
Yes. So we've had that question in various forms of it like what's clinically meaningful for fracture reduction. I think clinically meaningful, most people say at least thirty percent, forty percent would be clinically meaningful. Bisphosphates are probably twenty percent or less, so anything like thirty four percent or better.
58m 4s
We don't have a sense now for sure what [indiscernible] the power would tell us. As I said before, when the curves separate, they're linear essentially. And so we saw them separate within two to three months of treatment. Which means when they get to even just 9%, 10% improvement in bone density, there's already a separation in frequency. But after that, though, it appears relatively linear which tells me then that the percent reduction on the slopes won't really change that much over time And therefore, don't think you can think about like, when you hit will determine what percent reduction you get.
58m 46s
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 much how many fractures accumulated in one arm versus the other.
58m 58s
To give you the power?
59m
Does that answer your question?
59m 2s
Yes. Yes, think so. It's helpful. Thank you.
59m 8s
Our next question is from Laurie Chico with Wedbush. Hi, thank you very much taking the question. 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? [indiscernible] it's going really well in Latin America, I think growing recognition of how much patients do. But don't know, Eric, if you had any thoughts on what you say about how wide growing in Latin America particularly well?
59m 51s
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.
1h 12s
So it's a little bit about word-of-mouth and propagation of that through the pipe. We don't have a particularly prominent patient diagnosis function in Latin America. There are certain doctors, I mean, employees 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, nine 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 means they're just [indiscernible] they want to get more and more on. When I went down to the meeting last year, [indiscernible] patients, it was clear difference from the very first meeting we did at launch. That every doctor had a story of how their kids were doing and were grateful and excited about it and we're happy to be able to do something for these kids. So think that mood is good. The fact we're getting adults on is great too, because we certainly had gotten primarily peds on originally.
1h 1m 17s
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. In Brazil. Brazil as well as in Mexico. Yes. That's what's really driven it for Brazil and Mexico, driven a lot of the increase in rather than just named patient approach. In Turkey, it's still under named patient. But same things happen. Once the doctor starts treating people to see what 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 and parents or friends of people find out and that's what a good drug will do.
1h 1m 57s
Even in an inpatient setting.
1h 1m 59s
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 think the investment in Latin America and the top tier team in Turkey have been rewarded by being able to build a really solid brewing business. [indiscernible] the company.
1h 2m 17s
And I think that just sets us up well for when we bring sitrusumab to the marketplace It will because I think there's a lot to OI everywhere as well.
1h 2m 27s
Thank you for the question.
1h 2m 30s
Our next question is from Jack Allen with Baird. Great. Thanks taking the questions and congratulations on the progress made over the course of the quarter. One more logistical one on cetrusumab. Have you pointed investors towards how many of the patients had twelve months of data at that first interim readout? It sounds like it was the minority of patients 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 cetrusumab, I wanted to ask you about any disclosures you've made on the impact that cetrusumab has had on bone pain. We recently did a call with a physician who mentioned bone pain is a key symptom for these OI patients and I'd love to hear any impacts etrasimod could have there.
1h 3m 11s
Thank you. Okay.
1h 3m 13s
I'll talk a little about the IA-one and then maybe you can touch on the the Impression Scale scores or a little bit about pain, I guess. So just to understand the enrollment curve, we had a lot of patients enroll in the last two to three months of that trial, right? Was very much a hockey stick So when we had the minimum was seven months at that time point, we had a lot of people who were at eight, nine, ten months, right, and a relatively smaller number at the twelve to seventeen month timeframe, relatively smaller tail, right. So the vast majority patients had less than a year at that time In order to get the majority to have a year, you would take another two months or three months from the 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.
1h 4m 10s
So it will be a significant difference in the number of patients that have let's say, exposure beyond the two to three month period where they get the bone effect So let's talk about something other infraxin. I think it's actually really important. It's true for Crysvita too that things other than the bones often are drivers. What starts thought from what we've seen in the Phase two data Yes. No, agree. Pain is a big part of this.
1h 4m 34s
And certainly very important to patients and 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 thirty six to look at this. But that's definitely following pain over the long term.
1h 4m 57s
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.
1h 5m 9s
I think yes, I would say to you based on how kids were feeling, like they're running, hey, want to go to sports and stuff. They were feeling different too. Mean, whether it's pain or fatigue or generally malaise, Phase two patients often got pretty energized, think, right? And so that's also what happened with Crysida, by the way. That's why Crysida to pick up was so fast, because Kids feel good, parents see it.
1h 5m 35s
And I think that's happening with OI too. I think when your bones get stronger, even a little bit stronger, your body feels it and you know it. So we're excited about it. When we look at how many patients we have for that program and the fact that it's more than even with XLH, it's pretty clear that this program should exceed what we've done with Crysvita. I think we'll launch more rapidly. We just of course have to get our IE2 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.
1h 6m 11s
Are very few times you get to do something amazing like that again and we're really thankful to have an opportunity to take on a bone disease like imperfecta and turn it around for patients in the future.
1h 6m 24s
Thank you for the question.
1h 6m 28s
Thank you.
1h 6m 29s
There are no further questions at this time. I'd like to hand the floor back over to Joshua Higa for any closing comments.
1h 6m 36s
Thank you.
1h 6m 37s
This concludes today's call.
1h 6m 39s
If there are additional questions, please contact us by phone or at irultragenyx dot com. Thank you for joining us.
1h 6m 47s
You may disconnect your lines at this time. Thank you for your participation.
Key Insights
Ultragenyx reported Q1 2025 revenue of $139M, a 28% increase over Q1 2024, driven by strong growth in Crysvita (25% YoY, 52% in LatAm/Turkey), and reaffirmed full-year 2025 revenue guidance of $640M–$670M (14–20% YoY growth).
Key pipeline updates: Phase III studies for UX143 (osteogenesis imperfecta) and Perfexa have completed at least one year of enrollment, with interim analyses underway; GTX102 (Angelman syndrome) Phase III is enrolling globally with data expected in 2026; DTX301 (OTC deficiency) Phase III completed enrollment and is on track for data readout within a year.
Regulatory progress: Two BLAs are in process—UX111 (Sanfilippo syndrome) is under FDA review with a PDUFA date of August 18, 2025, and DTX401 (GSDIa) BLA submission is on track for mid-2025 following successful manufacturing qualification.
Operating expenses for Q1 2025 were $282M, with a net loss of $151M ($1.57/share); cash and equivalents stood at $563M as of March 31, 2025. Net cash used in operations is expected to decrease in the remaining quarters, supporting the company’s pathway to full-year GAAP profitability in 2027.
Clinical highlights: UX143 Phase III interim and final analyses are expected mid- and late-2025, with strong confidence in achieving clinically meaningful fracture reduction; Angelman pivotal study enrollment is on track for completion in 2025; DTX401 crossover data show sustained clinical benefit; and UX701 (Wilson disease) is advancing to pivotal stage with protocol amendments to optimize efficacy assessment.
