Q4 2024 Ultragenyx Pharmaceutical Inc Earnings Call
Speaker Change: Good afternoon and welcome to the Ultrademic 4th Quarter and Full Year 2024 Financial Results Conference Call.
Speaker Change: At this time, all participants are in a listen-only mode. At the end of the prepared remarks, you will have an opportunity to ask questions during the Q&A portion of the call. It is now my pleasure to turn over the call to Joshua Higa, Vice President of Investor Relations. Please go ahead.
Speaker Change: Joining me on this call are Emil Kakkis, Chief Executive Officer and President, Erik Harris, Chief Commercial Officer, Howard Horn, Chief Financial Officer, and Erik Crombez, Chief Medical Officer.
Joshua Higa: I'd like to remind everyone that during today's call, we will be making forward-looking statements. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. Please refer to the risk factors discussed in our latest SEC filings. I'll now turn the call over to Emil.
Emil Kakkis: Thanks Josh and good afternoon everyone. 2024 was a pivotal year for the companies. We advanced six late-stage programs in serious genetic conditions, most without any approved therapies, while also expanding access and growing revenue from our four commercial products worldwide.
Emil Kakkis: In the middle of the year, we increased our guidance for total revenue and now confirmed that we exceeded the upper end of that range for 2024.
Emil Kakkis: After filing our first BLA for San Filippo gene therapy earlier than planned, we now expect to have a second BLA for GSD1A gene therapy submitted to the FDA in mid-2025. And if both are approved, we would have six commercial products on the market.
Emil Kakkis: Combine that progress with the expected phase 3 data on UX143 and osteogenesis imperfecta.
Emil Kakkis: and expected full enrollment of our Phase III for GHEX-102 for Angelman syndrome, we are set for a strong year of value creation, greater than any year in our company's history.
Emil Kakkis: Our international growth in 2024 was particularly impressive. We successfully launched EFKISA in Europe, Canada, and Japan, while broadening access to our other commercial therapies in Latin America, Canada, and Turkey.
Emil Kakkis: We've also been working within these regions to establish clinical trial sites, prepare drug submissions with regulatory authorities, and bring our therapies into more geographies through named patient programs.
Emil Kakkis: We're looking forward to another year of strong global revenue growth in 2025, supported by multiple products in launch mode globally. This progress sets us firmly on a path toward full year gap profitability in 2027.
Emil Kakkis: In January, I discussed in-depth our priorities for this coming year, so I will use our time today to focus on our UX111 program for Sampleepo Syndrome, which has the potential to be our next approved product and our first commercial gene therapy program.
Emil Kakkis: Last week, we presented important new clinical data at the World Symposium in San Diego that were also included in our BLA submission last December.
Emil Kakkis: We filed for accelerated approval based on the substantial and sustained decrease in levels of heparin sulfate and supraspinal fluid or CSFHS following treatment with UX111.
Emil Kakkis: CSFHS is what I call a disease-caused biomarker because it's directly responsible for disease pathology and progression. It's not just a random measure associated with a disease, it is the disease.
Emil Kakkis: These new data show that a sustained reduction in CSFHS exposure
Emil Kakkis: is statistically associated with significant continued growth in the Bayley-3 cognitive raw score for the subdomains of cognition, receptive communication, and expressive communication when compared to natural history data, which show a climb during this age period.
Importantly...
Emil Kakkis: We also saw that older children with more advanced disease at the time of treatment
Emil Kakkis: were able to retain clinically meaningful functional abilities, including communication, ambulation, and self-feeding.
Emil Kakkis: fall in treatment with US-111 when the Bayley score is not an effective measure.
Emil Kakkis: As we stand in the release, we know from caregivers, clinicians, and others that stabilizing disease so that a child can retain or even slow down the loss of key skills like walking independently, communicating, and self-feeding has profound impact on their quality of life.
Emil Kakkis: The earlier we treat, the better is the long-term outcome and in the long run newborn screening will identify patients at birth and potentially enable an optimal treatment outcome.
Thank you for joining us. Thank you.
Speaker Change: Whether treatment from birth or later in life, these gains or retention of function with UX111 treatment are remarkable compared with the progressive loss of function expected in these patients.
Emil Kakkis: These results give me confidence that UX111 will be a successful product once approved with the potential to make a meaningful difference for patients with Sanford Leopold Syndrome Type A and their families.
Emil Kakkis: Our US-111 program also serves as a strong example of how we are leading and driving changes for the field.
Emil Kakkis: Our progress in San Filippo and the progress of other companies in the MPS field is made possible by FDA's willingness to accept CSFHS as a primary biomarker endpoint.
Emil Kakkis: Last February, we joined patient advocates, regulators, academics, and industry representatives in a workshop hosted by the Reagan-Udall Foundation to discuss qualifying biomarkers in support of rare disease regulatory pathways.
Emil Kakkis: This was an opportunity to take decades of work by academic researchers and clinicians in neuropathic MPS diseases and put together a body of information to provide support for leveraging accelerated approval to change the paradigm for drug development in these diseases.
Emil Kakkis: given my long history working on treatments for MTS diseases, including four of the five currently approved enzyme therapies in the U.S.
Emil Kakkis: This was an incredible achievement and opens up the possibility of accelerated development for the broader rare disease community, especially those impacted by metabolic diseases of the brain.
Emil Kakkis: We're pleased and thankful to see the FDA's focus on the rare disease over the past year with the advancement of first-ever treatments, some of which were at risk of being shelved entirely. We will continue our advocacy and engagement efforts to advance rare disease regulatory policy.
Emil Kakkis: With that, I'll turn the call over to our Chief Commercial Officer, Erik Harris, to provide a more detailed update on the progress across our commercial portfolio.
Thank you, Emil, and good afternoon, everyone.
Speaker Change: 2024 was a strong year for the Perspita franchise. Both the Kiara Karen team in the U.S., Canada, and Europe, and our team in Latin America and Turkey delivered outstanding results.
Emil Kakkis: and led to the revenue beat, raise, and beat that Emil mentioned earlier.
Emil Kakkis: I'll start with Crisfida in Latin America, where we need the commercial operations.
Emil Kakkis: In 2024, our team generated approximately 290 start forms that led to approximately 250 patients on reimbursed therapy.
Emil Kakkis: We now have approximately 750 patients on commercial products in the region as the team continues to exceed our expectations.
Emil Kakkis: Similar to what we saw in the United States, once doctors in Latin America see how well their patients are doing on therapy, they frequently write prescriptions for their other patients.
Emil Kakkis: Growth in the region has accelerated following successfully negotiating reimbursement from the Brazilian and Mexican authorities, the two largest payers in the region, and continued expansion in other South American countries.
Emil Kakkis: In the U.S., our partner, Kiawa Kirin, is leading commercialization and had a strong fourth quarter driven by growing underlying demand.
Emil Kakkis: Over the course of the year, the number of start forms generated exceeded our expectations, as did the number of patients on reimbursed therapy.
Emil Kakkis: We believe this confirms there are still a large number of patients who could benefit from this therapy and gives confidence there are still meaningful opportunities to grow this product.
Moving on to DeJovee.
Emil Kakkis: Growth of new STAR forms in the fourth quarter continued to steadily increase. In 2024, our team generated approximately 120 STAR forms that led to approximately 105 new patients on reimbursed therapy across the U.S.
Emil Kakkis: This brings the total, since launch in 2020, to almost 575 patients on reimbursed therapy. The split between pediatric and adult patients continues to be approximately 65% peds and 35% adults.
Emil Kakkis: The number of new prescribers continued to grow in the fourth quarter, with approximately half writing more than one prescription.
Emil Kakkis: For DERJOVI across the EMEA region, revenue is a result of named patient sales requests. There are over 250 patients treated under MPS across 14 countries in the region.
Emil Kakkis: The majority of demand is in France, but we are receiving an increasing number of requests from other countries in the EMEA region, including the Middle East.
Emil Kakkis: The demand for this product is quite strong in this region, especially given where we are not actively marketing the therapy and simply responding to named patient requests.
Emil Kakkis: I'll close with a few comments on Abkiza, which we have been launching outside of the U.S. over the past year or so.
Emil Kakkis: In the EMEA region, we have patients from all of the major countries, including France, Italy, Germany, Austria, and the Middle East.
We now have treated approximately 190 patients across 14 countries.
Emil Kakkis: This is a result of our commercialization efforts or responding to named patient requests as we continue to successfully navigate the country-by-country pricing negotiations.
Emil Kakkis: In Japan, the team continues to build on the launch momentum following the pricing and reimbursement approval that we received last year. We expect Japan to contribute more meaningfully to their total revenue as we launch APKISA and our future programs in this country.
Emil Kakkis: As I have mentioned on previous earnings calls, we continue to expect quarter-to-quarter variability in revenue.
Emil Kakkis: primarily due to uneven ordering patterns for Krispita and Latin America. But we remain confident in the growing underlying demand for all of our products around the world.
Emil Kakkis: Our teams were excited to deliver strong results in 2024, and we are looking forward to potentially commercializing two or three new products in the coming year or so.
Speaker Change: In the U.S., our Inborn Errors of Metabolism team that is currently commercializing Dojovi and Mefsevi look forward to being able to promote UX111 and DTX401 as transformational gene therapies once approved.
Speaker Change: For UX143, we will need to build out the U.S. team in preparation for a potential launch, and we will be able to use our deep institutional knowledge from our successful CRISPR-Eta launch where there is 90% overlap in call points.
Speaker Change: With that, I'll turn the call to Howard to share more details on our financial results and guidance.
Howard Horn: Thanks, Erik, and good afternoon, everyone. I'll focus on full year 2024 corporate results and our 2025 guidance.
starting with total revenue.
Howard Horn: For 2024, we reported $560 million, representing 29% growth over 2023.
Howard Horn: CRISFIDA contributed $410 million, including $249 million from North America, $135 million from Latin America and Turkey, and $26 million from Europe.
Howard Horn: In total, this represents 25% growth over 2023. If you focus on Latin America and Turkey, where we are responsible for generating sales, this represents 78% growth over 2023.
Howard Horn: Turning now to DeJolvi, it contributed $88 million, which represents 25% growth over 2023.
Howard Horn: EFKISA contributed $32 million as demand continues to build following launches in our territories outside of the United States.
Howard Horn: and Mepsevi contributed $30 million as we continue to treat patients in this ultra-rare indication.
Howard Horn: Total operating expenses for the year were $1.1 billion, which included R&D expenses of $698 million, SG&A expenses of $322 million, and cost of sales of $77 million.
Howard Horn: For the year, net loss was $569 million or $6.29 per share.
Howard Horn: As of December 31, we had $745 million in cash, cash equivalents, and marketable securities.
In 2024, net cash used in operations was $414 million.
Howard Horn: Importantly, in 2025, we expect reduced net cash used in operations compared to 2024.
Howard Horn: As you remember from prior years, we typically use more operating cash in the first quarter than in the other three quarters because it includes items like the payment of annual bonuses.
Howard Horn: This year, the first quarter will also include $45 million in payments for two milestones that were achieved in the fourth quarter of 2024.
Howard Horn: one for the initiation of our Angelman Phase III study and one for a sales milestone for EFKESA.
Howard Horn: We will continue to prioritize expense management and focus our investments on the execution of our upcoming commercial launches and advancing our Phase III programs.
Howard Horn: Shifting to revenue guidance for 2025, total revenue is expected to be between 640 and 670 million, which represents 14 to 20 percent growth over 2024.
Howard Horn: 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 at KISA in Europe and Japan.
Howard Horn: CrisVita revenue is expected to be between 600 or excuse me 460 and 480 million which includes all regions and all forms of CrisVita revenue to Ultragenyx.
This range represents 12 to 17 percent growth over 2024.
Howard Horn: As a reminder, in the first quarter of the year, we restart at the lowest tier of our royalty structure in North America.
Howard Horn: The Jolvi revenue is expected to be between $90 and $100 million, which represents 2 to 14% growth over 2024.
Howard Horn: As in prior years, our Dijovi projections represent a blend of faster growth in countries where we commercialize and lower growth in countries where we respond to named patient requests.
Howard Horn: With that, I'll turn the call to our CMO, Erik Crombez, who will provide an update on our key clinical data readouts expected this year.
Erik Crombez: 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.
Erik Crombez: starting with UX 143 for the treatment of osteogenesis imperfecta. The phase 3 orbit study is progressing well and the safety profile is similar to what was observed in phase 2.
Erik Crombez: Based on the Phase 2 data we previously shared, we are confident that this study will show a clinically and statistically significant reduction in annualized fracture rate at either the second interim analysis or the final analysis.
Erik Crombez: The ORBIT and COSMIC studies will both have an interim analysis mid-year, after all patients have been on therapy for at least 12 months, and the alpha spend for each study will be 0.01.
Erik Crombez: If IA-2 for ORBIT is not achieved, the study will proceed to full study analysis in the fourth quarter.
Erik Crombez: Moving to GTX 102 for the treatment of Angelman syndrome. Enrollment in the phase 3 ASPIRE study is going well and we are on track to complete enrollment in the second half of this year.
Erik Crombez: Based on the strong interest from physicians and patient families for this transformative therapy, and with our team's commitment, I have confidence that we will be able to enroll the planned 122 patients in less than one year.
Erik Crombez: In parallel, we are also working to initiate our Phase 2-3 study, AURORA, that will study younger and older patients and those with other mutations.
Erik Crombez: Once this protocol is through the regulatory process, we will share additional design details.
Erik Crombez: Shifting now to our gene therapy programs and starting with UX111 for the treatment of MPS3A.
Emil Kakkis: Emil already shared the latest data we presented last week and we expect to receive confirmation of our BLA acceptance shortly.
Emil Kakkis: This will also confirm our PDUFA date, which we expect to be in the second half of the year. The biomarker data and the newly presented clinical improvements in multiple domains show the impact this therapy can have for families and patients who otherwise face a lethal disease.
Emil Kakkis: I look forward to completing this work and to the launch of our first gene therapy product.
Emil Kakkis: Next, DTX-401 for the treatment of glycogen storage disease type 1a.
Emil Kakkis: Work on the BLA filing is going well, and we are on track for FDA submission mid-year.
Emil Kakkis: We have talked about the decision to move manufacturing for this program to our facility in Bedford, Massachusetts. And while this required some additional work and time, it enabled far greater control over the manufacturing process, improved quality, and reduced costs.
Emil Kakkis: Finally, I'll touch on DTX-301 for the treatment of ornithine transcarbamylase deficiency.
Emil Kakkis: As noted in our press release today, we have completed enrollment in the Phase 3 study with a total of 37 patients randomized one-to-one to placebo or DTX01.
Emil Kakkis: and will now evaluate the reduction and removal of standard of care after unblinding given the reluctance of patients and doctors to stop alternate pathway medications in a blinded study.
Emil Kakkis: This reluctance stresses the severity of this disease with the irreversible damage caused by high ammonia levels and the need for a one-time treatment option that establishes the normal ability of the urea cycle to metabolize ammonia.
The primary endpoints are unchanged.
Emil Kakkis: and our one response as measured by change in 24-hour ammonia levels during the first 36-week blinded period compared to placebo patients, and 2% of responders who were able to remove alternate pathway medications and protein-restricted diets.
Emil Kakkis: This responder endpoint will now be assessed across the whole group of patients, including placebo crossover patients, for up to 64 weeks.
Emil Kakkis: The new design increases the power of the study by assessing ammonia early, where reductions occur rapidly, and then assessing the diet and drug removal by evaluating all patients compared to the baseline in the longer follow-up period.
Emil Kakkis: These changes allow us to reduce costs and to shorten the overall timeline by ending enrollment at 37 patients and making the study more patient-centric.
Emil Kakkis: The protocol amendment reflects the real-time feedback we heard from patients and physicians about the fear of removing life-saving treatments in a blinded, placebo-controlled study. As a patient-engaged company, we need to hear their concerns during trial conduct and now have made a better trial design with their feedback.
Emil Kakkis: I'll now turn the call back to Emil to provide some closing remarks.
Emil Kakkis: Thank you, Erik. In 2025, we'll continue building on the outstanding clinical and commercial execution that put us in place to transform into a leading rare disease company with a commercial financial engine that supports this clinical pipeline.
Emil Kakkis: We have a number of near-term catalysts, which Erik has already covered, and I expect to have three potential approvals in the next year or so. As a company, LGX has arrived. We are creating the paradigm for the next generation of rare disease companies changing the future for rare disease patients.
Emil Kakkis: With that, let's move on to your questions. Operator, please provide the Q&A instructions.
Thank you.
Emil Kakkis: Thank you. We will now be conducting a question and answer session.
Emil Kakkis: As a reminder, if you would like to ask a question, please press star 1 on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star 2 if you would like to remove your question from the queue.
Emil Kakkis: For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys.
Emil Kakkis: So that we may address questions from as many participants as possible, we ask that you limit yourselves to one question and one follow-up. If you have additional questions, you may re-queue, and time permitting, those questions will be addressed. One moment, please, while we poll for questions.
Speaker Change: Thank you. Our first question comes from the line of Tazeen Ahmad with Bank of America. Please proceed.
Speaker Change: Hi, guys. Thanks for taking my question. So, mine is going to be on OI and how we should be thinking.
Speaker Change: You've talked about this many times, but Emil, if you could give some color about your confidence in the second interim read being sufficient to stop the study versus needing to go to the third interim. I know you've expressed overall confidence in the trial design and the likelihood of success.
Speaker Change: But we'd like to hear your thoughts about how you're thinking about the importance of the study You know being stopped at the second interim. Thanks
Thank you.
Speaker Change: Great, well, you know, we believe the second item certainly has a much greater chance of
Speaker Change: of hitting than the first one because it's a 0.01 threshold and because the patients will have had at least 12 months of treatment to allow the groups to separate.
Speaker Change: So there's certainly greater confidence in the second interim, but we feel confident one way or another the trial is going to end and we'll be successful this year. We've been watching the Phase II patients, they're doing great, and we feel very good about how Phase III conduct is going. So we have more confidence in the second interim than we did in the first.
Speaker Change: But it's either the second interim or the end of study, but we have a product that's going to work and we're excited about that product and bringing it to OI patients.
Thanks operator. Let's move to the next question.
Thank you.
Speaker Change: Our next question comes from the line of Salvin Richard with Goldman Sachs. Please proceed.
Salvin Richard: Good afternoon, thanks for taking my question. Just a follow-up to the first one here, maybe help us understand if it doesn't hit on the second interim what would those reasons be or what are the risks to that and then how long would we have to wait for the final analysis? Thank you.
Salvin Richard: Well we said the second will be mid-year. For it not to hit at 12 months it's usually in rare disease that have to do with amount of variation and the number of fractures. If there's a lot of variation there's a wide range of patients baseline fracture rates because we have some type 3, 4, and then type 1 patients.
Salvin Richard: large variation could could create some a challenge but I I think that so far we feel like the trials is proceeding as expected.
Salvin Richard: So, if it doesn't hit in the second interim, we'd expect to release data by the end of the year on the final assessment for the trial.
Thank you.
Thank you.
Our next question comes from Amrupan Rama with J.P. Morgan.
Please proceed.
Speaker Change: Hi guys, this is Priyanka An for Anupam. Thanks for taking our question. Once ORBIT hits, will you immediately prepare to file or wait for the cosmic analysis to finish and add it to the application? Thanks.
Speaker Change: If orbit hits, first of all, we will have the data clean and locked, and there won't be a need to follow for any longer, so it will be more quickly to reach final analysis.
Speaker Change: and to file. And so, compared to interim mouse one, there's probably just a one-quarter delay in filing off the quarter two. So, it should come more quickly after that, at that result.
Thanks, operator. Let's move to the next one.
Speaker Change: Our next question comes from the line of Jenna Wang with Barclays. Please proceed.
Jenna Wang: Thank you. Sorry, I will ask another OI question. Given the study complete enrollment on May 1st, 2024, is it fair to assume June-July timeframe? You should share the second interim update. And then, how would you communicate with the investor in the case the study didn't hit the stats?
Jenna Wang: And in the case the study hits stats, would you need to take extra time to analyze the data and therefore share the update a little bit later?
Jenna Wang: Yes, so we will be managing the second term like the first. A DMC will meet and look at the data and...
Jenna Wang: If they don't inform us that it hit, then we know it didn't hit, and we will expect to communicate to the street where we're at at that point in time.
Jenna Wang: Fair to consider June-July. I guess that's possible, but we haven't set the time. We said mid-year, which is in that range, but we're not committing to an exact time. We're trying to keep you guessing a little bit, Gina.
Did I miss, did I get your questions?
Jenna Wang: Yeah, so if you hit it, that means, like, we'll share with us a little bit later since you will need to take a few more weeks to analyze the data.
Jenna Wang: The DMC would see the data. We would find out it hit
Jenna Wang: We would then get to unblind and look at the data ourselves and relatively sooner after that we would expect to put out results. It won't be like the first time where we had to go two months more, where we had to take two more months. So it should be relatively quicker to come out with the actual result, top-line results anyways.
Okay, great. Thank you.
Speaker Change: Thank you. Our next question comes from the line of Yarin Weber with TD Cowen. Please proceed.
Speaker Change: Great, thank you. I also, shockingly, have a 143 question. In the ORBIT study, are you stratifying, just remind us, type 1, 3, and 4 between the two arms?
Speaker Change: And then secondly, when you look at the primary of fracture rates, do you have a secondary looking fracture rates by type, underlying type? Thank you.
Erik Crombez: Yeah, so in general, we do stratify, but it's mainly for its overall fractures and its age. But I'll let Erik talk about the way we're approaching it.
Erik Crombez: Yeah, so because the primary endpoint is annualized fracture rate, you want to stratify by fracture rate. So while that definitely will kind of encompass the different types there, the strict stratification is based on fracture rate coming into study.
Thank you.
Erik Crombez: So type 2 and 4 may have a higher fracture rate, but we're focusing on that. Doing it by the 3s and 4s and 1s, it didn't look like that was gonna be the right way to go, as fracture rate was a better way.
Erik Crombez: So we're also looking at ages, so there's an age balance between the groups. And regarding the other endpoints,
Erik Crombez: We are looking at total fractures, not just the fractures minus fingers, toes, skull.
Erik Crombez: Those total fractures are an endpoint, and the subset between subtypes, I'm sure we'll do analysis sensitivities on that in there, but it's not a formal secondary endpoint.
Speaker Change: Thank you. Our next question comes from Miko Novavich with Citi. Please proceed.
Speaker Change: Hi, this is Rena on for y'all. Thanks for taking my question
Speaker Change: I just wanted to ask one on OI. I was just wondering if, at the point of hits, whether it be the second interim or the final, if we would learn maybe retrospectively, like any kind of retrospective analysis you'd share on how close the studies were to hitting at either the first interim or the second interim, respectively.
Speaker Change: He wants to tell you what happened at IA1 or IA2 later.
Speaker Change: Do you have like personal bets with other investors about that to try to settle?
Speaker Change: I don't know if we would show with the other items. We haven't decided that. I think what matters is if the study hits, the study works, and the drug works. And right now, I'm not committing whether I'm going to show all the little bits and pieces of what happened.
Speaker Change: We're pretty comfortable that, look, we, if you look back, we presented phase two data, remember, at six months and showed you a 67% reduction with a p-value of 0.04.
Speaker Change: And then we did the same group of patients, but now at 14 months, right, and they had 67% reduction in fractures, but now they had a P-value of 0.014.
Speaker Change: That is a reasonable model for what would be going on here, that the groups are separating, you just need to go a little further to get the p-value where it needs to be and hit the threshold set. So I'd look at that phase 2 data we've already shown you as kind of a model for what's going on. But right now we put out data, we'll put out the data we have, and I don't know if we'll put out the rest.
to settle scores, but thank you.
Speaker Change: Thank you. Our next question comes to the line of Maura Raycloth with Jefferies. Please proceed.
Speaker Change: Hi, this is Farzeen Anformuri. Just to clarify an earlier point, you mentioned that if the second interim hits, you do the final analysis quickly, so just wondering if you need to supplement the final data package with the 18-month data or not.
Speaker Change: Now if we hit at the second interim then the package will include all those patients with at least 12 months of data. The range though would be like from 12 there are some patients at that point would have 20 months.
Speaker Change: It's 12 to 20 months of exposure time. So it's a pretty long period of time, actually. It's almost two years in all patients. So 12, that will be, I think, plenty for that. I didn't mention, someone asked about orbit, or I mean, cosmic earlier. Cosmic will be evaluated in parallel. And.
Speaker Change: But we won't close out COSMIC if ORBIT doesn't hit. If ORBIT hits, then we'll look at COSMIC, but the data will be ready to be looked at. But we wouldn't stop COSMIC if ORBIT doesn't hit, because we need ORBIT in order to file.
Speaker Change: But we wouldn't hold out filing to get 18-month data. We'd file with the data we had and we've had that discussion with the FDA.
Got it.
Speaker Change: Thank you. Our next question comes in line of June Lee with Jewish Securities. Please proceed.
Speaker Change: Thanks for taking our questions. If the OI study goes to completion in 4.2, does that imply that the magnitude of the set may not be as great as expected? And in that case, how competitive would Cetruzumab be compared to bisphosphonates?
Speaker Change: Actually, it would not mean it's not as great. If you remember earlier when we had...
Speaker Change: six-month data and a 14-month data phase 2, they both had 60% reduction of fractures.
Speaker Change: What it has to do with is the two lines have to separate, so the biggest reason is there's too much variation, and those variations might cause a delay, but the actual rate separation could very well be 67%.
Speaker Change: It's just you have a lot of patients that may have 10 fractures a year or one fracture a year in the same study, and some of the ones may not have fractured, for example, and then during, for whatever reason.
Speaker Change: And so it's really more about separating the two groups, but I don't think it necessarily tells you what the percent reduction is. We think if you listen to some of the KOLs that 50% or greater reduction of fracture is considered really important. And frankly, when we look at patients after a year.
15-16 months of therapy. We've had some for longer.
Speaker Change: They are, many of them are not fracturing at all at some point, so we feel very comfortable that the long-term outcome here is greatly reduced fractures.
Speaker Change: Whatever the number is, but I think the biggest issue is the variation in how much fractures are occurring in each group.
Speaker Change: and that wide range that probably exists that will impact how the study reads out.
Speaker Change: We are using co-variables to manage that variation, but that would be the number one reason. So, I don't think you can conclude the drug is not working well if we go to the end. Remember, the original plan here was to do a two-year study.
Speaker Change: The only reason we felt we could go sooner is because the percent reduction was higher than we thought and that the speed of response was faster.
Speaker Change: Those are the things that give us confidence that we can go earlier.
Speaker Change: But we've been moving this up from 18-month to two-year studies.
Speaker Change: right, down to what we're talking about now, which is a 12.
Speaker Change: Thank you. Our next question comes to the line as Jeff Hung with Morgan Family. Please proceed.
Jeff Hung: Thanks for taking my question. I just wanted to clarify and make sure I understood correctly. You talked about how the phase 2 data and the 0.014, 0.014, but just for situation, would the ORBIT phase 2 portion have hit with the second interim analysis criteria? And if not, how were the baseline fracture rates different from the phase 2 portion? Thanks.
Speaker Change: Right, so that was the difference. You're asking how close does that reflect what's going on.
Speaker Change: The Phase II patients are fairly similar in terms of the entry criterion for fractures are the same. They're made up of Type I 3s and 4s. Phase III has somewhat more 3s and 4s.
Speaker Change: But not a dramatic difference. So it's a very comparable population, age range, types included, and baseline fracture requirements. So I think that those are reasonable ways to look at what phase 3 should be happening. And so the only question has to do with how, you know, the variation in
Speaker Change: in the population, how big is it, and how much it moves in the timeframe. But, you know, I think the data from phase two are a reasonable model for what's happening.
Okay, I hope you found that helpful.
Thank you all.
Thank you.
Speaker Change: Thank you. Our next question comes from Linus Joseph Schwartz with WeRigPartners. Please proceed.
Speaker Change: Hey all, this is Will. I'm for Joe. Thanks for taking our questions today and congrats on the progress this quarter. I have one on OI and then a follow-up on UX111. So just first for OI, wondering if you could provide any more color on the characteristics of the patients in the phase two that had fractures while they were on treatment.
Speaker Change: Do we know the subtype of these patients, and how does that impact your thinking about the phase three, which has, just as you said, a few more severe patients? Thank you.
Speaker Change: There were 17 type 1's and they were some of the ones that had fractures were type 1's, so it's not like
Speaker Change: Having type 3s and 4s made more fractures necessarily. The 3s and 4s tend to have higher fracture rates.
Speaker Change: But the ones that did have fractures were not necessarily, like, only type 3s and 4s. For example, it was, I think they were mostly type 1s, as I recall.
Speaker Change: So there's no, I would say, a pattern there that would tell you something about how phase three, I think, actually, there's no pattern.
Speaker Change: Probably more impressive is how much all three types respond very comparably in bone marrow density improvement. I think that was the most interesting thing that we saw. Do you have a follow-up with 111?
Speaker Change: Great, yeah, thank you. Yeah, just on 1.11, you know, since it's going to be the first gene therapy launch for you guys, how are you thinking about pulling learnings from other programs or experiences that had success or maybe not were that successful in their commercial rollout, and how does this kind of set you up for other gene therapy launches down the line, including 4.01? Thank you.
Speaker Change: We're a very dynamic commercial organization, and we're used to launching new things. The disease has never been treated before us, but we've essentially done everything on time. I'll let Erik say a few words, if you'd like. But the...
Erik Crombez: We are going to be looking at what everyone is doing, for sure, and our goal will be to get our work with payers so upfront, get to understand the value proposition, the data we have in hand, and to allow them
and hopefully to create as rapid and prompt
Erik Crombez: a pattern of review and approval, because urgency and time really matter to these kids, and a six-month delay is not.
Erik Crombez: allowable. This is a very severe disease, so I would look at UX111 as being more like Zolgenslan SMA in terms of life or death and no alternative treatment. I do think there's an urgency. I think the payers will respect that. We just need to make them aware of it.
Erik Crombez: And I don't know, Erik, is there anything, a simple thing you can touch on on how we're going about the launch? Yeah, we've been in close contact with the treatment centers, potential treatment centers, because remember we're in with those customers now with
Erik Crombez: both DiGiovi and Mevsevi. And so we're learning a lot about the coordination that would be required between the patients and the physicians for delivery of the gene therapy.
So we're ready. We'll be ready to go.
Erik Crombez: We'll certainly want to learn for successful launches of Ilgenza and there's a lot of people out there that have that knowledge and I think there's an advantage now coming out now with several products out there knowing what works what hasn't and I think the truth about rare disease about gene therapy launches it's all about urgency.
Tazeen doesn't have a treatment, it's lethal.
Erik Crombez: Their adoption is going to be much faster and we think UX111 fits that mold like Silkenzma.
So we're looking forward to a good launch.
Erik Crombez: And we're excited about the opportunity of treating this disease. They've been sampling pigments, waiting forever for something, and this is the first time it's actually happening. And I know they're grateful and excited about finally something being done for their kids.
Thank you.
Thank you.
Speaker Change: Our next question comes from line of Kristen Kluska with Cancer Fitzgerald. Please proceed.
Speaker Change: Hey, everyone. This is Rick Miller on for Kristen. Thanks for taking our questions. We're going to mix it up a little bit and ask about OTC deficiencies. So, just to better understand the amended protocol that you talked about today, when the patients in the Phase III are in the initial 36-week blinded period, are they still eligible for titrating down on ammonia scavengers and diet control, or would that just be an option in the following unblinded period? And then based on the natural history for the disease, is there any good understanding?
Special thanks.
Very well.
Speaker Change: We already have treated a lot of patients and know that none of them wanted to reduce. So, we kind of know during the line-up period none of them would reduce, so we're...
Speaker Change: If you have the option or not, it doesn't matter. The truth is it's a little cleaner if no one would, but since they have it, it doesn't matter. So we're going to look at ammonia baseline relative to later. What we know is we allowed up to 200 micromole in the study.
Speaker Change: So, there will be a number of patients that have significantly elevated ammonias, which on a chronic basis are not good, and these ammonias we're talking about are 24-hour curves, right, so they're monitoring during a 24-hour cycle that go up and down.
Speaker Change: So we expect from our phase two data that should drop within six weeks and very rapidly drop to normal range. So we'd expect that the patients that have high immunities that are clearly abnormal range, that clearly impair cognitive function right above 80 or so.
Speaker Change: should normalize. And that's why we think we'll have a lot of power.
Speaker Change: So, I think that the degree of ammonia change in those that are elevated will be clearly from abnormal cognitive impairing type range and into a normal range where you expect greater clarity of thought and function. We'll be monitoring those things as well.
Speaker Change: The problem, of course, with removing their drugs is they're so afraid of crashing and because it can't happen suddenly that, well, just reserving that to after they get unblinded.
Speaker Change: And so we'll actually have the same endpoints, really the same trial, it's just that we'll unblind people after 36 weeks and then they can start titrating, but we'll get blinded data, controlled blinded data for that period, which...
we think will be clinically meaningful ammonia reductions.
Speaker Change: I don't know if there's anything else I missed, Erik, that you'd add. Well, I would just want to draw the parallels to GSD-1A. I mean, you know, we had a lot of reluctance there in the blinded period to be aggressive with reduction of corn stars, but once all patients rolled over to long-term follow-up in an unblinded setting.
Speaker Change: We saw further reduction in all patients and very closely mimicking what we saw in the phase two. So I think, you know, we're confident we'll see something similar here in this phase three and get much closer to a duplication of what we saw in the phase two, which was done in an unblinded manner.
Speaker Change: And the percent responders is complete responders, so they have to get off their drug and diet control to be considered complete responders, which is what the FDA preferred.
Speaker Change: I think having all patients be assessed that way I think is a will help the power of the study because there's actually more patients and doing it within patient comparison is a lot more powerful than doing it to group comparison.
Speaker Change: So thanks for the question on OTC and breaking up the OI domination.
Next.
Speaker Change: Thank you. Our next question comes from Luka Isil with RBC Capital.
Please proceed.
All great. Thanks so much for your question.
Speaker Change: I guess we'll revert back to the meeting here and maybe ask a question on OI. What's the latest thinking on duration of therapy? Assuming the trial is successful, do you think that the FDA will cap the duration of therapy to 12 months as they have done for
Speaker Change: Rheumatoid Arthritis, Chronic Dosing with No Cap, and second, very quickly, can you just remind us why for Angelman, running a shame control trial is the better way to go versus a placebo control trial? Thanks so much.
Thank you for watching.
Speaker Change: Sure, so on the duration, it's one of the first things we did in taking over the program is not make the assumption that 12 months makes any sense for these patients.
Speaker Change: and what we're learning already is that the assumption that 12 months that the treatment stops working essentially you don't need to go longer and that you then lock it in with bisphosphate, that model is true for maybe 80 year old women with osteoporosis.
Speaker Change: But when you're talking about these kids, their bones want to resorb. The kids that stop treatment, the adults that stop treatment before that were with OI patients
in the asteroid study started losing ground.
Speaker Change: And it's pretty clear to us that OI is just different. And when we look at patients long-term treated, they continue to gain ground in BMD for quite a bit of time.
Speaker Change: And our view is that we should be treating till optimal clinical effect, and our expectation is that we'll become a chronic treatment. And it's possible down the road that they could go to maintenance therapy where they get less frequent dosing. But it's pretty clear that one year is...
You're not done after one year.
Speaker Change: Most of these kids probably need at least two years of continuous therapy, if not more.
Speaker Change: and I think the data we have is already telling us that that's right, that the patients are continuing to benefit.
Speaker Change: When you have a bone marrow density, for example, that's minus 2 to minus 4 Z-score, while they gain a lot of ground in one year, they're continuing to gain ground in the second year, clearly, linearly. So, we're very comfortable that we're making the right call here, and that's one of the things that's important as a company, is that we don't just follow the rules.
Speaker Change: What everyone says. We're looking at what's really going on and look at the science and the science says these kids need to get treated longer And we're going to continue to do that. We'll work with the agency in the long term
Speaker Change: the right balance of bone production versus bone resorption, which they need that constant stimulation to make that set point right.
Speaker Change: Now, like an osteoporosis patient, which you're artificially trying to up their bone production, but they don't have an intrinsic problem like these kids do, right? So, when you have an neuroangenic cause, I think it's just a different biologic situation, and we think chronic treatment's the right answer.
So, second question on Angevin.
Speaker Change: Oh the Angeman, sham versus placebo. We actually proposed placebo originally. The FDA at the time said their assessment was potentially unethical to have to do sham treatment or placebo treatment. We opted not, and we'd heard something similar from EMA, so we opted to go with
Speaker Change: The sham, just because we felt there was an ethical or regulatory burden there that we have to go through, not them, just them, just them, but IRBs, but I think you could do the study either way. I don't think it's going to matter.
Speaker Change: Sham has more work, right? Yeah, I mean the real difference between sham and placebo is we in the placebo controlled patients We will not be injecting artificial CSF so that really is
Speaker Change: The practical difference that comes out in the sham design, so it's really not a big significant difference between the two designs, but you don't need to administer artificial CSF.
Craig
Speaker Change: Thank you. So we've managed all the prospects of blinding and execution for that. It's a bit more work to do sham, but it is...
Speaker Change: We felt I didn't want to battle a pill with IRBs or EMA or other regulatory authorities regarding the issue of injecting placebo and having every injection be an injection in these kids. But I don't think it's going to matter and it won't make a difference in the meaning of the treatment.
Speaker Change: We feel comfortable that the design is going to get us where we need to go.
Super helpful. Thanks so much.
Speaker Change: Thank you. Our next question comes from Ina B. Savacco with Evercore ISI. Please proceed.
Hi, thanks for taking the question.
Speaker Change: A question on the variability in OI. In your work, you know, preparing for the trial and assumptions, can you talk about any sort of registry or database
Speaker Change: views you've got on variability. Is there some way to describe that? And I guess, is there a trend, like if a patient has?
Thank you so much.
Well, we know from our Phase 2 baseline data
Speaker Change: you know, 0.7 or 1 fracture a year and some I think they're up as high as 6 or 7 fractures a year. Is that right, Eric? Yeah, so
That's a pretty wide range of baseline fractures.
Thank you.
Speaker Change: We know in the younger patients, they tend to have more fractures.
Speaker Change: So, if you talk about the really young ones, the younger you go, the more fractures they have. So, those are the factors.
Speaker Change: With that wide a range, you have to imagine that you have to power the study to reduce fracture across a wider array of change. We think that we are well powered to do that in the design and
Speaker Change: If you look at what happened in phase 2 over a period of time, really the majority of the patients have not had any more fractures, stopped having fractures completely.
Speaker Change: And certainly, as we put in our deck, one of the doctors said they've not seen a single fragility fracture since starting STREETS map. So we're comfortable that we're going to be able to show the delta. I was just saying, if you ask me why would interim two not work?
Speaker Change: Well, it's a question of variation is usually the thing in these studies, but we feel comfortable that with enough time they will separate and you'll get an important result for this disease.
Speaker Change: Thank you. Our next question comes to the line of Ed Aker with A.T. Rainwright.
Please proceed.
Speaker Change: Hi director and everyone, this is Thomas. We have asked a couple questions for Ed. Thank you so much.
So perhaps switching gears to 1.02...
Speaker Change: As you work to finalize the design for the Phase II-III oral study, can you discuss some factors between the two patient populations that would differentiate the study from ASPIRE? And then, taking a bigger picture, overall strategy of 102.
Speaker Change: Do you also expect Aurora would have data to supplement VOA that we expect to be based on aspired data, as expected sometime in the second half of 2026?
Okay, so...
Speaker Change: On GTX-12, the main study, to remind everyone, the main study is as far as focused on deletion patients ages 4 to 17, which is the same population we studied in Phase 2. So the Aurora study is simply the support labeling across
different age groups, and different genotypes.
Speaker Change: For under 4, we'll have some patients treated open-label, we'll look at the same endpoints, but just show, does under 4-year-old patients, do they respond comparable to what we saw in their Phase 2 or in what's in Phase 3?
Speaker Change: Our experience in the rare disease world that you can expand the label for age simply by treating a small number of patients in an open label format and collect data that's comparable to your blindness set.
for the
Thank you. Thank you.
Speaker Change: We will also do that for some older patients. For the non...
Speaker Change: The non-deletion types, we'll look at patients in the main range and the point will be the same to look at the different genotypes.
Speaker Change: collect enough patients to show it's safe to just give it to them and that using comparable endpoints
Speaker Change: we can demonstrate a magnitude effect that is comparable. In our experience, that kind of data would allow us to support labeling. So our intent is to have...
Cut of data from Aurora in time for BLA filing.
Speaker Change: But we would probably still continue to collect data in Aurora during the review process in case the agency wanted more.
Speaker Change: And the other advantage of Aurora is that we can also do it in other territories around the world, giving more doctors exposure to the treatment, and to gain support for regulatory findings that might occur in other parts of the world.
Speaker Change: So those are some of the factors of how Aurora will work.
Speaker Change: Thank you. The next question comes to the line of Aaron Weaver with TD Cowan. Please proceed.
Aaron Weaver: Yes, thanks for taking my follow-up. I just got a couple, Emil. The first one, I'm 401, so given that you're fully enrolled now and the primaries are 36 weeks...
Aaron Weaver: And then you want blind. Is there a chance that we'll get the data that the first sort of the primaries this year? And then secondly, I think I misheard, but I just want to double-check. It sounds like you're saying in Cosmic you'll do an interim analysis now mid-year as well.
Aaron Weaver: Is that, indeed, is that going to be the first intro for that? And I think you mentioned that 12 months, but with a .01 alpha, but I thought that was referring to orbit, so I just want to double check the interim analysis on COSMIC.
Sure, so I think you're speaking of 301 for OTC.
Speaker Change: Yes, so the 36-week data could provide data. We're not saying when yet. It depends a little on the last patient in and having 36 weeks, etc. But it could be. We haven't provided the exact timing of that data yet to you. For OI,
Speaker Change: When we run the interim on the orbit study, we'll run an interim on cosmic at the same time. We'll look at orbit. If orbit's positive, then we'll look at the cosmic data. If orbit's positive, then we'll look at cosmic, and it also is being looked at at a 0.01p value.
Speaker Change: which would give us the full label. And we also think it gives us labeling against bisphosphonates, right, as well as versus placebo, right, so they both studies add value to the commercial launch of the program.
Thank you.
The point of one for both studies. Okay.
Thank you.
There are no further questions.
I'd like to pass the call back over
to Joshua Higa.
Thank you all for any closing remarks.
Speaker Change: Thank you. This concludes today's call. If there are any additional questions, please contact us by phone or at IR at Ultragenyx.com. Thank you for joining us.
This concludes today's teleconference.
Speaker Change: You may disconnect your lines at this time. Thank you for your participation.
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