Ultragenyx Pharmaceutical Q1 2025 Earnings Report

Ultragenyx Pharmaceutical EPS Results

• Actual EPS: -$1.57
• Consensus EPS: -$1.54
• Beat/Miss: Missed by -$0.03
• One Year Ago EPS: -$2.03

Ultragenyx Pharmaceutical Revenue Results

• Actual Revenue: $139.29 million
• Expected Revenue: $145.98 million
• Beat/Miss: Missed by -$6.69 million
• YoY Revenue Growth: +28.00%

Ultragenyx Pharmaceutical Announcement Details

• Quarter: Q1 2025
• Date: 5/6/2025
• Time: After Market Closes
• Conference Call Date: Tuesday, May 6, 2025
• Conference Call Time: 5:00PM ET

Ultragenyx Pharmaceutical (NASDAQ:RARE), a biopharmaceutical company, focuses on the identification, acquisition, development, and commercialization of novel products for the treatment of rare and ultra-rare genetic diseases in North America, Latin America, Japan, Europe, and internationally. Its biologic products include Crysvita (burosumab), an antibody targeting fibroblast growth factor 23 for the treatment of X-linked hypophosphatemia, as well as tumor-induced osteomalacia; Mepsevii, an enzyme replacement therapy for the treatment of children and adults with Mucopolysaccharidosis VII; Dojolvi for treating long-chain fatty acid oxidation disorders; and Evkeeza (evinacumab) for the treatment of homozygous familial hypercholesterolemia. The company's products candidatures include DTX401, an adeno-associated virus 8 (AAV8) gene therapy clinical candidate for the treatment of patients with glycogen storage disease type Ia; DTX301, an AAV8 gene therapy for the treatment of patients with ornithine transcarbamylase; UX143, a human monoclonal antibody for the treatment of osteogenesis imperfecta; GTX-102, an antisense oligonucleotide for the treatment of Angelman syndrome; UX111, an AAV9 gene therapy product candidate for the treatment of patients with Sanfilippo syndrome type A, or MPS IIIA, a rare lysosomal storage disease; UX701, for the treatment of Wilson disease; and UX053 for the treatment of glycogen storage disease type III. Ultragenyx Pharmaceutical Inc. has collaboration and license agreement with Kyowa Kirin Co., Ltd.; Saint Louis University; Baylor Research Institute; REGENXBIO Inc.; Bayer Healthcare LLC; GeneTx; Mereo; University of Pennsylvania; Arcturus Therapeutics Holdings Inc.; Solid Biosciences Inc.; Regeneron; Abeona; and Daiichi Sankyo Co., Ltd. The company was incorporated in 2010 and is headquartered in Novato, California.

Ultragenyx Pharmaceutical Q1 2025 Earnings Call Transcript

Key Takeaways

• Ultragenyx reported Q1 revenue of $139 million, up 28% year-over-year, reaffirmed full-year guidance of $640–670 million (+14–20%), and maintained a path to GAAP profitability by 2027.
• The commercial franchise continued to gain momentum, with Crysvita delivering 25% growth (52% in Latin America & Turkey), alongside steady contributions from DeJolvi, EVKYSA and Mepsevii across global markets.
• In rare disease development, both Phase III studies of UX143 (setrusumab) for osteogenesis imperfecta have >12-month data locked and are entering the second interim analysis, aiming for a clinically significant reduction in fracture rates.
• Several key trials and regulatory filings remain on track, including global enrollment and 2026 data for GTX-102 in Angelman syndrome, DTX-301’s enrollment completion in OTC deficiency with data readout next year, and a mid-2025 BLA submission for ZTX-401 (GSD1a) alongside a PDUFA date of August 18 for UX111 (Sanfilippo).
• R&D investments totaled $166 million in Q1, including $45 million in milestone payments, underscoring Ultragenyx’s commitment to advancing one of the most productive pipelines in rare disease.

Presentation

[Operator]

Good afternoon, and welcome to the Ultragenyx First Quarter twenty twenty five 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 and 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 - Investor Relations at Ultragenyx Pharmaceutical]

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 Kakas, 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.

[Joshua Higa, VP - Investor Relations at Ultragenyx Pharmaceutical]

Please refer to the risk factors discussed in our latest SEC filings. I'll now turn the call over to Emil.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Thanks, Josh, and

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

good afternoon, everyone. In the first quarter, we continued to make meaningful progress across one of the most productive commercial and development pipelines in rare diseases. Our commercial team delivered a strong quarter that puts us in a position to have another year with meaningful revenue growth. Our early investments in high performing teams have helped generate substantial revenue growth, while we commercialize our products outside of The United States. At the same time, we are preparing to launch our next set of programs in The U.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

S. And around

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

the world.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

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 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 first quarter and is on track to read out data over the next year. The UX701 Wilson disease, the study is now enrolling the fourth dose finding cohort that will enable dose selection and transition to the pivotal stage.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

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 GSD1a 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. The UX-one hundred eleven for Sanfilippo syndrome BLA under review by the FDA is progressing on schedule as expected. It's not our standard practice to go into the details of regulatory interactions, but I think it's meaningful at this current time for investors to be aware that our interaction with the FDA on the UX111 BLA review thus far remain on track. Last month, we had our mid cycle review meeting that occurred on the standard timeline.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

We also know that inspections of the manufacturing facilities and clinical sites have been scheduled according to normal cadence and are currently underway. We remain on track for the PDUFA action date of August 18. Going forward, we don't plan on giving the details of all our regulatory interactions, but we did want to share enough detail for you to remain confident as we are that the DUX 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.

[Erik Harris, Executive VP & Chief Commercial Officer at Ultragenyx Pharmaceutical]

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 twenty twenty four. 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 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.

[Erik Harris, Executive VP & Chief Commercial Officer at Ultragenyx Pharmaceutical]

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 adults have exceeded the

[Erik Harris, Executive VP & Chief Commercial Officer at Ultragenyx Pharmaceutical]

Make up more than half

[Erik Harris, Executive VP & Chief Commercial Officer at Ultragenyx Pharmaceutical]

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 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.

[Erik Harris, Executive VP & Chief Commercial Officer at Ultragenyx Pharmaceutical]

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 DERJOVY across the EMEA region, there are over two sixty patients treated under named patient sales across the region.

[Erik Harris, Executive VP & Chief Commercial Officer at Ultragenyx Pharmaceutical]

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 EFKYSA, which we began commercializing in our territories outside of the '23. In the EMEA region, we have patients on reimbursed therapy from the majority of major countries. We now have treated approximately two fifty patients, adding more than 50 since the beginning of the year across 15 countries in the region.

[Erik Harris, Executive VP & Chief Commercial Officer at Ultragenyx Pharmaceutical]

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 FTISA revenue to contribute more meaningfully to total revenue as we continue to successfully launch this important product outside of The United States. As I have mentioned on previous earnings calls, we continue to expect quarter to quarter variability in revenue, primarily due to uneven ordering patterns for Crysvita in LatAm, but we remain confident in the growing underlying demand for all of our products around the world.

[Erik Harris, Executive VP & Chief Commercial Officer at Ultragenyx Pharmaceutical]

With that, I'll turn the call to Howard to share more details on our financial results and guidance.

[Howard Horn, Executive VP of Corporate Strategy & CFO at Ultragenyx Pharmaceutical]

Thanks, Eric, and good afternoon, everyone. 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, we 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, 50 5 Million from Latin America and Turkey and $7,000,000 from Europe.

[Howard Horn, Executive VP of Corporate Strategy & CFO at Ultragenyx Pharmaceutical]

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 the DEJOLVE, it contributed $17,000,000 consistent with its expected steady growth trajectory. EVKYSA 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.

[Howard Horn, Executive VP of Corporate Strategy & CFO at Ultragenyx Pharmaceutical]

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. 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 two development milestone payment I mentioned earlier.

[Howard Horn, Executive VP of Corporate Strategy & CFO at Ultragenyx Pharmaceutical]

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 $640,000,000 and $670,000,000 which represents 14% to 20% growth over 2024. Drivers include increasing demand for our products in Latin America, continued penetration of the pediatric and adult XLH markets in The U. S.

[Howard Horn, Executive VP of Corporate Strategy & CFO at Ultragenyx Pharmaceutical]

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. This range represents 12% to 17% growth over 2024. DeJolvi 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.

[Howard Horn, Executive VP of Corporate Strategy & CFO at Ultragenyx Pharmaceutical]

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 Krombez, who will provide an update on our key clinical data readouts expected this year.

[Eric Crombez, Chief Medical Officer & Executive VP at Ultragenyx Pharmaceutical]

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 UX-one hundred forty three for the treatment of osteogenesis and Perfecta, 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. The Orbit and COSMIC studies will both have an interim analysis midyear after all patients have been on therapy for at least twelve months.

[Eric Crombez, Chief Medical Officer & Executive VP at Ultragenyx Pharmaceutical]

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-one hundred one 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.

[Eric Crombez, Chief Medical Officer & Executive VP at Ultragenyx Pharmaceutical]

We've 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 midyear. During the crossover period, patients demonstrated even greater reductions in total daily cornstarch at their last visit compared to baseline in both the ongoing DTX401 group and the placebo crossover to DTX401 group.

[Eric Crombez, Chief Medical Officer & Executive VP at Ultragenyx Pharmaceutical]

Patients in the DTX401 group demonstrated a sixty percent 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 daily cornstarch at their last visit, where the mean duration on therapy with DTX401 was sixty nine weeks. Patients in both groups have demonstrated statistically and clinically meaningful reductions in daily cornstarch requirements, demonstrating continued benefit from this gene therapy over time. 01 also continues to demonstrate a consistent and acceptable safety profile with no new safety signals identified.

[Eric Crombez, Chief Medical Officer & Executive VP at Ultragenyx Pharmaceutical]

The manufacturing process at our Bedford, Massachusetts facility is going well, and we recently successfully completed our process performance qualification runs. While the tech transfer from a CDMO to our facility was done quickly and efficiently, it did impact our BLA submission timing. We were able to capitalize on this opportunity to collect more clinical data, resulting in an even stronger clinical and CMC filing package that we will submit to the FDA midyear. Finally, I'll touch on UX701 for the treatment of Wilson disease. As noted in our press release today, we have recently begun enrolling patients into a fourth dosing cohort at a dose of four thousand thirteen.

[Eric Crombez, Chief Medical Officer & Executive VP at Ultragenyx Pharmaceutical]

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 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. 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.

[Eric Crombez, Chief Medical Officer & Executive VP at Ultragenyx Pharmaceutical]

Specifically, we 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.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Thank you, Eric. Over the first part of the year, we made tremendous progress executing on all fronts. Patients in both UX-one 43 for OsteoSimperfecta studies have now been enrolled for at least twelve months, and this enables our teams to start the process of cleaning, locking the databases that will be shared with the data monitoring committee in the next few months. The feedback we hear from investigators of patients in the Phase II portion of the ORBIT study gives us confidence the treatment effect with cetuximab 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 $640,000,000 to $670,000,000 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 III studies enrolling or reading out data, we are in prime position to lead the future of rare disease medicine.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

With that, let's move on to your questions. Operator, please provide the Q and A instructions.

[Operator]

Thank you. We'll now be conducting a question and answer session. In the interest of time, we ask the participants limit themselves to one question and one follow-up and reenter the queue for additional questions. One moment please while we poll for questions. Our first question is from Yaron Werber with TD Cowen.

[Yaron Werber, Managing Director, Senior Biotechnology Analyst at Cowen and Company]

Thank you so much for taking my question. Not surprisingly, it's going to be about setrusumab, the second interim analysis. And sort of one question in two parts. Maybe the first one, Emil, you've talked recently about dispersion in the study. And that's something that when we look at the prior data in the Phase II, the dispersion is not really shown.

[Yaron Werber, Managing Director, Senior Biotechnology Analyst at Cowen and Company]

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? Thank you.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

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, that there is a variation in the analyzed fracture rate at baseline. And we know we have people who can have more than three fractures a year, and it's less fracture rate greater than three and some less.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

So we stratified 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 baseline. Now the statistical method we're using the negative binomial will capture the AFR as a baseline as a co variable, meaning will 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.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

So we're doing a number of things that will help reduce variation, but there is a lot of variation in severity and fracture frequency and we think we've done what we can. But that might be one reason why you might not hit IE2. We think we have a good shot of hitting IE2 based on everything we know. But we are very strongly positive on the trial whether IE2 or the end is going to be successful. So let's talk about the fracture reduction.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

We announced Phase II data after six months or so and showed a sixty seven percent reduction with a p value of 0.04. Then 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. So you might be wondering, well, how is the number the same? I would look at this as think of it as a line of accumulated fractures. The accumulated fractures in one group is going up at a steep rate and the slope of the other line is only 67% less, right?

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

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.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

But by the second time, we'll have run longer that we should have much better separation. So from that analysis, it suggests that we could hit it I. Two, 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 placebo and compared to their current year on treatment.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

And with the negative binomial, you get the same mid-60s percent kind of reduction all right, with a good P value. So just to be clear, if you do it by the method we're using in Phase III, you get a very similar result. Just because some people wondered whether the different statistical approach would matter. So, variability is an issue. Dispersion or statistical version of it, could go into.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

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.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

All right. Let's go on.

[Operator]

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

[Tazeen Ahmad, MD - US Equity Research at Bank of America]

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

[Tazeen Ahmad, MD - US Equity Research at Bank of America]

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.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Right. Well, it won't be the next assessment is the final assessment for the study and that p value threshold will be 0.04. So it would be a lot easier to hit 0.04. So we think that we will hit one or the other based on our experience what we've seen. I don't think we could miss the 0.04 at that point with eighteen months of time.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

But as always in rare disease programs, thing you always are battling against is variation, variability in patients. But based on the profound difference in bone marrow density change that we see that happens within two to three months and the fracture rate effect happens within two to three months, we feel pretty good about IE2 hitting, but confident about overall the study hitting even at the end, if not at the IE2. So I can't tell you a reason why, but variation is always a thing that can create complexities. But given that the 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 24.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

So I think we've got a lot of power in there, but we've done everything we can to manage variations. So I feel good about we'll hit it this year either at 0.01 or 0.04 after eighteen months.

[Operator]

Our next question is from Gena Wang with Barclays.

[Gena Wang, MD - Biotech Equity Research at Barclays]

Thank you for taking my questions. Maybe a little bit switch gear, little bit the non fundamental questions. I think it was a recent CBAR nomination of Vinay Prasad. And I think there is a lot of uncertainties. We saw massive sell off in the biotech sector.

[Gena Wang, MD - Biotech Equity Research at Barclays]

And so Abhi, 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? I 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 patients has a baseline bisphosphonate and then the washout period in the late enrollment period, you did skip the washout period.

[Gena Wang, MD - Biotech Equity Research at Barclays]

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?

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Very good. So, 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. I think we'd have to anchor back to the fact that Carrie has been talking about the importance of rare disease approvals and thinking how to improve and accelerate the process or reduce the time of development. So we'll have to anchor to that discussion and point he's made and see what Forsyth does. I think for our own program, for UX-one 11, we have lots of clinical data in the program.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

I'm less concerned about it because of the fact we have clinical data showing efficacy in addition to the biomarker data. And so I think for us right now, we're not concerned. But I think for industry at large, it'd be important for accelerated approval to be available for a lot of the gene or cell therapies. And it would be important that McCarrie's public commitment to try to move these things forward. It's something that, he follows through on.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

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, more than eighty percent to ninety percent or something like that were on bisphosphonates in the study, right? Correct.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Yes. And the washout timeframe is in the one to two year period. So we'd expect the placebo patients to be have steadily declining frac bisphosphonates effect and therefore steadily potentially increasing fracture rate as their bone marrow densities decline. But we don't think that effect is really a meaningful effect compared to the dramatic effect on bone marrow density that's going to happen with cetuximab, right? Where for the five to twelve group, we had a twenty nine percent increase.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

The bone marrow density improvement, the effect on the other groups will not be nearly so large. So what it would do is both groups would have a loss of bisphosphate effect over the period. But remember, setrusumab arm will also have some anti resorptive effect from the drug itself. So if anything, what this will do is increase the rate of separation as time goes on and improve the power of

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

the study longer it goes.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Do you have anything else to add to that, Yusef?

[Eric Crombez, Chief Medical Officer & Executive VP at Ultragenyx Pharmaceutical]

Just that we didn't count on this. When we were designing the study and powering the study, we did not account for that effect. So in any sense, that could be considered an upside.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Yes. Very good. Thank you.

[Operator]

Our next question is from Salveen Richter with Goldman Sachs.

[Lydia Erdman, Biotech Equity Research Analyst at Goldman Sachs]

Hi, this is Lydia on for Salveen. Thanks so much for taking our questions and congrats on all the progress. Just maybe another one on cetrusumab. 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? Much.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Yes. So when we the 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 inform us that the study needs to go to the end, we'll also inform the Street that the study is continuing to the end. So if you haven't heard from us because the decision hasn't happened yet and a decision either is moving forward to the final assessment or it's ending at the interim will be clear. We haven't 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 a potential filing from that data set.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

So the time to data would be faster than we have said for the IE1 where we had only partial lock and we had to continue the trial. So it would be relatively soon we talk about data. Now if IE2 is positive, then the COSMIC study will be evaluated. If Orbit is negative, then we won't unblind the COSMIC data and we'll wait for both studies to go to the next assessment. Okay?

[Lydia Erdman, Biotech Equity Research Analyst at Goldman Sachs]

Thanks so much.

[Operator]

Our next question is from Anupam Rama with JPMorgan.

[Malcolm Kuno, Analyst at JP Morgan]

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

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

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

[Eric Crombez, Chief Medical Officer & Executive VP at Ultragenyx Pharmaceutical]

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.

[Eric Crombez, Chief Medical Officer & Executive VP at Ultragenyx Pharmaceutical]

Yes, our global sites are active and beginning to screen and dose patients.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

So all sites are active.

[Malcolm Kuno, Analyst at JP Morgan]

Excellent. Thank you.

[Operator]

Our next question is from Kristen Kluska with Cantor.

[Kristen Kluska, Equity Research Analyst at Cantor Fitzgerald]

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

[Kristen Kluska, Equity Research Analyst at Cantor Fitzgerald]

So is there anything you're able to share?

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

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

[Eric Crombez, Chief Medical Officer & Executive VP at Ultragenyx Pharmaceutical]

No, I think that covers it.

[Kristen Kluska, Equity Research Analyst at Cantor Fitzgerald]

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.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

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 in the same day or not. We'd like to keep you guessing a little bit, right?

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Why make it too easy?

[Operator]

Our next question is from Yigal Nochomovitz with Citi.

[Yigal Nochomovitz, Director at Citigroup]

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? And then also this is a very specific question, but what exactly is the tolerance on these p values? I mean, we're talking about some pretty small numbers here. So I mean, hypothetically, if it's like 0.011 in on the second interim, is that a fail or a win?

[Yigal Nochomovitz, Director at Citigroup]

It's I mean, I would I think I know, but I'm not sure actually. So I was just curious if you could clarify that level of detail and whether you were ever told the p value for the first one, the first interim? Thanks.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

So on the OI types, think we've disclosed before that in the Phase II study, were seven Type IIIs and IVs and 17 Type I. 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 about half the patients are Type three and four approximately there 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. All right.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Now for tolerance, we haven't set that like how many sig figs of significance. Honestly, I don't have an answer for you. But I would say if it's like 0.015 or 0.016, 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 if there was an issue. But so that's the basic the tolerance question.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

And then the last one was whether it was the P value and the others we haven't provided a P value. We were not aware of the P value nor provided one in the interim the first interim. We were just told that it was study was continuing and no result. So what we know from the prior analysis of Phase two though that the p value was 0.014 at fourteen months. So we think there's a reasonable chance of hitting IE2, 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.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

All right. Thank you, Gal.

[Yigal Nochomovitz, Director at Citigroup]

Thanks.

[Operator]

Our next question is from Joseph Schwartz with Leerink.

[Will Soghikian, Vice President - Equity Research at Leerink Partners]

Hey, all. This is Will on for Joe. Thanks for taking our question and congrats on the progress this quarter. So one for us on Angelman. Now with three ASOs that are in or nearing pivotal development, including the one from Roche that was recently revived, are you thinking about the evolution of this market?

[Will Soghikian, Vice President - Equity Research at Leerink Partners]

And do you see a room for multiple treatment options? And how do you think these assets can potentially further differentiate themselves? And how do you think patients are going to be making decisions from a clinical trial or commercial therapy perspective? Thank you.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Thank you. Well, we are not usually 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.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

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 ASOs. But I do believe our drug is the most potent and has shown that and I think we've shown the best long term data, continuous improvement over long periods of time that has been shown for the INS molecule. The Roche molecule is sort of coming back into development.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

I am not concerned about. I think that that drug is even less potent and has other questions marks. So if there's more than one out there, I think it will depend on efficacy and what people can show. I do think that we have because we expanded our Phase two study and we have almost 70 patients on drug, that we're going to have a pretty big body of kids have been on drug several years. I think how those kids are going to doing are going to be probably even more impactful than the Phase three study.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

That will be what people want to see, what's my future like for my kid, if I'm on this. And we know from some of the early patients on there, the first one that actually had words, she had a few words in the first year, but now she's speaking a few dozen words and has continued to gain ground over time. So I think that experience will be really important. I do think we're in the best position to be the leader in the ASO space. And my hope going down the road that the top three ASO treatments will be our first product, then our second improvement and then the third next gen that comes out.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

And because we intend to be the leaders in the arrangements.

[Operator]

Our next question is from Lisa Bayko with Evercore ISI.

[Liisa Bayko, Managing Director at Evercore ISI]

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 then take some time to analyze the data and come back to us with the data?

[Liisa Bayko, Managing Director at Evercore ISI]

Or is that all in one press release? Thanks.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Yes. So on the timing of data, because I think people may some people have had an unrealistic expectation that you would clean, lock and analyze the data in a couple of weeks or something. But this is 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 an international study to clean and lock a database, plus there will be some time to analyze and have a DMC meet and disclose. So at the time we find the result, we will there'll be a much shorter time than we had before in terms of seeing what the data are.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

We haven't yet precisely said whether we'll disclose it together at once or whether it 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 IA-one where we had some other questions. So hopefully that gives you an idea, Elyse, of how it's going to flow. Okay.

[Liisa Bayko, Managing Director at Evercore ISI]

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

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Yeah, what happened to IE1 is that even if the interim was positive, the regulatory authorities wanted to have the majority of patients have at least twelve months of data. So we would have had to keep running the study for a couple of 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 for a couple of months 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 and locking at that time.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

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 much faster because we're going to clean lock the whole database this time and we would be able to release top line data sooner than we would have at IA1.

[Operator]

Our next question is from Luca Izzi with RBC Capital.

[Luca Issi, Senior Biotechnology Analyst at RBC Capital Markets]

Great. Thanks so much for taking my question. Congrats on the progress. Maybe just one more on OI just to be super, super clear. In a scenario where you actually don't hit the second interim look, will the DSMB share with you the P value?

[Luca Issi, Senior Biotechnology Analyst at RBC Capital Markets]

Just wondering whether you will have a sense of whether you missed by a narrow margin or not. And then maybe related, is it fair to assume that the PRV for OI is possible only if you hit in a second interim look? My understanding is that you need to get approved by the end of twenty twenty six in order to get the PRV given that there's sunsetting that program. Any context there? Much appreciated.

[Luca Issi, Senior Biotechnology Analyst at RBC Capital Markets]

Thanks so much.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

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 PI3 designation and we'd have to get approved by October.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

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 accelerate things if need be.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

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 111 gets approved for Sanfilippo and if DTX401 gets approved for GSD1a. So I don't think there's anyone with potentially three PRVs still in play without the reauthorization. I do believe the bill will get reauthorized. I think we've had the assurance of that is true, but I think right now there's some of the other matters that are top of mind in Capitol Hill that that one will take a little while before it will come up.

[Joshua Higa, VP - Investor Relations at Ultragenyx Pharmaceutical]

To clarify

[Joshua Higa, VP - Investor Relations at Ultragenyx Pharmaceutical]

that, the 143 is in October of twenty twenty six. We need approval by October 2026.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Right.

[Joshua Higa, VP - Investor Relations at Ultragenyx Pharmaceutical]

Next question. Thanks, operator.

[Operator]

Our next question is from Joon Lee with Truist Securities.

[Mehdi Goudarzi, Biotech Equity Research Analyst at Truist Securities]

Hello. Good afternoon and thanks for taking our question. This is Mehdi on for Joon. So I go on OI and follow-up Igor's question on composition of OI types. So do you agree that sacituzumab's MOA benefits the Type I patients more than Type IV and III?

[Mehdi Goudarzi, Biotech Equity Research Analyst at Truist Securities]

This is the question.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Well, I know there's been some academics saying that, but and I know 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 don't have abnormal collagen. Therefore, if we just make more bone, it'll be okay. And the Type three and four have abnormal collagen and therefore it's not improved. But that's not actually what we saw.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

We see both of them have improved reduction of fractures. And in fact, the ones fractures we did see were in type one patients, I 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 bone greater bone strength and reduced fractures. So it actually works in all three. And historical clinical view of OI is going to change because the truth is that even with abnormal collagen, the bones can be strengthened, we believe in these patients and that's what we've seen and that's in the data from Phase two.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

And so 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.

[Mehdi Goudarzi, Biotech Equity Research Analyst at Truist Securities]

Thank you very much.

[Operator]

Our next question is from Maury Raycroft with Jefferies.

[Maury Raycroft, Equity Research Analyst at Jefferies]

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

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Yes. So we've had that question in various forms of it like what's clinically meaningful for fracture reduction. I think for clinically meaningful, most people say at least 30%, forty % would be clinically meaningful. Dysphosphates are probably 20% or less, so anything like 30%, forty % or better. We don't have a sense now for sure what the power would tell us.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

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 910% improvement in bone density, there's already a separation in fracture frequency. But after that, though, it appears relatively linear, which tells me then that the percent reduction on the slopes won't really change that much over time. And therefore, I don't think you can think about like when you hit will determine what percent reduction you get. I think you have to think of it more as a slope and the time is will just depend how far apart the two lines are, how much how many fractures accumulated in one arm versus the other to give you the power.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Does that answer your question?

[Maury Raycroft, Equity Research Analyst at Jefferies]

Yes. I think so. It's helpful. Thank you.

[Operator]

Our next question is from Lorie Chico with Wedbush.

[Dylan Shindler, Biotechnology Equity Research Associate at Wedbush Securities]

Hi. Thank you very much for taking the question. This is Dylan on for Lorie 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?

[Dylan Shindler, Biotechnology Equity Research Associate at Wedbush Securities]

Or I guess what is unique about patient identification efforts in these regions?

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

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

[Erik Harris, Executive VP & Chief Commercial Officer at Ultragenyx Pharmaceutical]

As I had stated in the opening remarks that patients are having a good experience with the product and physicians are

[Erik Harris, Executive VP & Chief Commercial Officer at Ultragenyx Pharmaceutical]

now treating more and more

[Erik Harris, Executive VP & Chief Commercial Officer at Ultragenyx Pharmaceutical]

of their patients to include adult patients in the LatAm region as well.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

So it's a little bit about word-of-mouth and propagation of that through the public. We don't have a particularly prominent patient diagnosis function in Latin America. There are certain doctors, I mean, employees that are doing patient fine, but it's not quite the same because we don't have the same tools in South America that we have in The U. S. Like we don't have the codes, nine codes, 10 codes and other things to help us.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

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 there. They want to get more and more on. When I went down to the meeting last year, the Latin America Brazilian meeting on these patients, it was clear difference from the very first meeting we did at launch that every doctor had a story of how their kids were doing and we're grateful, excited about it and we're happy to be able to do something for these kids. So I think that mood is going to add the fact we're getting adults on is great too, because we certainly had gotten more primarily peds on originally.

[Erik Harris, Executive VP & Chief Commercial Officer at Ultragenyx Pharmaceutical]

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

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Yes, in Brazil.

[Howard Horn, Executive VP of Corporate Strategy & CFO at Ultragenyx Pharmaceutical]

Brazil as well as in Mexico.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Yes, that's what's really driven it for Brazil and Mexico driven a lot of the increase in uptake rather than just named patient approach. In Turkey, it's still under named patient, but same things happen. Once the doctor starts treating people to see what happened, over a period of the year, they see how their bones doing, how the kids are doing, they get adamant about getting more kids on and parents or friends of people find out and that's what a good drug will do. Even in an inpatient setting, people hear about a story and they all want to get something for their kids. So we're excited about that continued growth of the product internationally.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

And I think the investment in Latin America and the top tier team in Turkey have been rewarded by being able to build a really solid growing business for the company.

[Erik Harris, Executive VP & Chief Commercial Officer at Ultragenyx Pharmaceutical]

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

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

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

[Operator]

Our next question is from Jack Allen with Baird.

[Jack Allen, Senior Research Analyst at Baird]

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 twelve 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.

[Jack Allen, Senior Research Analyst at Baird]

And then also on cetrusumab, 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

[Jack Allen, Senior Research Analyst at Baird]

you.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Okay.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

I'll talk a little about the IA-one and then maybe you can touch on the Impression Scale scores or just 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? It was very much a hockey stick. So when we had the minimum was seven months at that time point, we had a lot of people who were at eight, nine, ten months, right, and a relatively smaller number at the twelve seventeen month timeframe, relatively smaller tail, right? So the vast majority of patients had less than a year at that time.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

In order to get the majority to have a year, you would take another two months or three months from when the cut was made. Does that make sense? So it's a very steep accumulation at the end. A lot of the patients were less than a year then, the majority were less than a year at the first interim. So it will be a significant difference in the number of patients that have, let's say, exposure beyond the two to three month period where they get the bone effect.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

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's our thought from what we've seen in

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

the Phase II data, Eric?

[Eric Crombez, Chief Medical Officer & Executive VP at Ultragenyx Pharmaceutical]

Yes. No, agree. Pain is a big part of this 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.

[Eric Crombez, Chief Medical Officer & Executive VP at Ultragenyx Pharmaceutical]

We are also doing a traditional SS36 to look at this, but definitely following pain over the long term. In Phase II, we did hear a lot of improvement there. Anecdotally, we have heard that patients have had a lot of improvement in pain scores.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Much did you take? I would say to you based on how kids were feeling like they're running, hey, I want to go to sports and stuff. They were feeling different too. I mean, it's pain or fatigue or generally malaise, face to face patients also got pretty energized, I think, right? And so that's also what happened with Crysida, by way.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

That's why Crysida, the pickup was so fast. Kids feel good, parents see it. And I think that's happening with OI too. I think when your bones get stronger, even a little bit stronger, your body feels it and you know it. So we're excited about it.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

When we look at how many patients we have for that program and the fact that it's more than even with XLH, it's pretty clear that this program should exceed what we've done with Crysvita. And I think we'll launch more rapidly. We just of course have to get our IE2 or a final data in hand and get to a file. But we're excited about the opportunity being larger than it is even with Crysvita. There's very few times you get to do something amazing like that again and we're really thankful to have an opportunity to take on a bone disease like osteogenesis imperfecta and turn it around for patients in the future.

[Emil Kakkis, Founder, President, CEO & Director at Ultragenyx Pharmaceutical]

Thank you for the question.

[Operator]

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 - Investor Relations at Ultragenyx Pharmaceutical]

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

[Operator]

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

Participants

Executives

• Joshua Higa, VP - Investor Relations
• Emil Kakkis, Founder, President, CEO & Director
• Erik Harris, Executive VP & Chief Commercial Officer
• Howard Horn, Executive VP of Corporate Strategy & CFO
• Eric Crombez, Chief Medical Officer & Executive VP

Analysts

• Yaron Werber, Managing Director, Senior Biotechnology Analyst at Cowen and Company
• Tazeen Ahmad, MD - US Equity Research at Bank of America
• Gena Wang, MD - Biotech Equity Research at Barclays
• Lydia Erdman, Biotech Equity Research Analyst at Goldman Sachs
• Malcolm Kuno, Analyst at JP Morgan
• Kristen Kluska, Equity Research Analyst at Cantor Fitzgerald
• Yigal Nochomovitz, Director at Citigroup
• Will Soghikian, Vice President - Equity Research at Leerink Partners
• Liisa Bayko, Managing Director at Evercore ISI
• Luca Issi, Senior Biotechnology Analyst at RBC Capital Markets
• Mehdi Goudarzi, Biotech Equity Research Analyst at Truist Securities
• Maury Raycroft, Equity Research Analyst at Jefferies
• Dylan Shindler, Biotechnology Equity Research Associate at Wedbush Securities
• Jack Allen, Senior Research Analyst at Baird