Ultragenyx Pharmaceutical - Q2 2024
August 1, 2024
Transcript
Operator (participant)
Good afternoon, and welcome to the Ultragenyx Second Quarter 2024 Financial Results Conference Call. At this time, all participants are in listen-only mode. At the end of the prepared remarks, you will have an opportunity to ask questions during the question and answer portion of the call. Vice President of Investor Relations, please go ahead.
Joshua Higa (Head of Investor Relations)
Thank you. We have issued a press release detailing our financial results, which you can find on our website at ultragenyx.com. Joining me on this call are Emil Kakkis, Chief Executive Officer and President, Erik Harris, Chief Commercial Officer, Howard Horn, Chief Financial Officer, and Eric Crombez, Chief Medical Officer. I'd like to remind everyone that during today's call, we will be making forward-looking statements. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. Please refer to the risk factors discussed in our latest SEC filing. I'll now turn the call over to Emil.
Emil Kakkis (CEO and President)
Thanks, Josh, and good afternoon, everyone. We've had an incredible first half of the year and look forward to sharing more with you today. On the commercial front, our strong revenue performance puts us on a trajectory to outperform our prior projections, and so we're raising our total revenue guidance range. We're happy with what this means for access to our drugs globally, and Eric and Howard will share more on the revenue details. Within our clinical pipeline, we've meaningfully advanced our late-stage program through multiple positive data readouts and successful and critically important regulatory interactions.
On the data front, in addition to the positive results we shared early this year on both UX111 in Sanfilippo syndrome and GTX102 in Angelman syndrome, we recently announced positive phase III results from the DTX401 gene therapy for the treatment of patients with Glycogen Storage Disease Type Ia, and additional long-term positive phase II results from the UX143 antibody for the treatment of patients with osteogenesis imperfecta. For GTX102 for Angelman syndrome, we announced the successful completion of an end-of-phase II meeting with the FDA, where we aligned on phase III study design and key endpoints to be evaluated. Our teams have been working with our study sites to initiate our global phase III study by the end of this year.
On UX111 for Sanfilippo syndrome Type A, we also reached agreement with the agency on a path forward to seek accelerated approval. The FDA has agreed that cerebrospinal fluid heparan sulfate is a reasonable surrogate endpoint to support submission of a BLA supported by our clinical data to date. Our next step is to finalize the details of our submission with the agency in a pre-BLA meeting, and we intend to submit this BLA later this year or early next. Collectively, this puts us in a position to have multiple regulatory marketing submissions and key clinical data readouts over the next six to 18 months, which is extraordinary.
I spent my career developing therapies in rare disease, and I can tell you I've never seen a rare disease company with the breadth and depth of opportunities we have ahead of us, nor with our ability to move all things, these things forward. These achievements are a direct result of our excellent execution across the company, from our committed employees and our best-in-class approach to rare disease drug development. It's a very exciting time for Ultragenyx. I'll now turn the call over to our Chief Commercial Officer, Erik Harris, to provide an update on the momentum across our commercial portfolio that has led us to raise our total revenue guidance for the year.
Erik Harris (EVP and Chief Commercial Officer)
Thank you, Emil, and good afternoon, everyone. I'll start with Crysvita's performance in the United States. The demand for Crysvita in the U.S. remained strong in Q2, 2024. Approximately 60% of the start forms came from adult patients and were prescribed by community physicians, with over 40 new prescribers in the quarter. This is encouraging, given adult penetration is in the low 20s and implies Crysvita has ample room to continue growing. We are confident in our full-year U.S. revenue projections, given the strength of the underlying demand. Shifting to Crysvita in Latin America, where we lead commercialization, our LatAm team delivered another successful quarter by adding approximately 60 new patients to Crysvita, totaling over 620 patients on reimbursed therapy since launch. Brazil is the largest market in Latin America and continues to drive the majority of revenue in the region.
That said, we are beginning to see more meaningful contributions from countries like Argentina and Mexico, supported by the underlying patient demand. As I mentioned on previous earnings calls, we expect quarter-to-quarter variability in LatAm revenue due to uneven ordering patterns, but remain confident in the underlying demand growth for our products. Moving on to Dojolvi. Growth of new start forms remains strong. In the U.S., we added approximately 30 start forms and 30 patients on reimbursed therapy, resulting in approximately 520 reimbursed patients since launch. The split between pediatric and adult patients continues to be approximately 65% peds and 35% adults. The number of new prescribers continued to grow, adding approximately 10 new prescribers in Q2 2024, with half of them writing more than one prescription. For Dojolvi across Europe and the MENA region, revenue is currently driven by named patient sales requests....
There are approximately 215 patients treated under NPS across 12 countries in the region. The majority of demand is from France, but we are receiving an increasing number of requests from other countries within the EMEA region, including the Middle East. As I have said before, 2024 is an important launch year for Evkeeza. In the EMEA region, we added approximately 60 new patients in the second quarter, who are being treated through NPS and regular reimbursement processes where we have approval. In Japan, the launch is starting, but has already gained meaningful contribution following regulatory approval in January and pricing and reimbursement approval in April. The team there has done an excellent job to map and identify a majority of patients in the country and has processed 35 start forms through the second quarter of 2024.
In our territories, we continue to receive positive feedback from the HoFH physician and patient communities, and they are all very excited to have Evkeeza as a treatment option. We expect demand for Evkeeza to continue growing as we bring this important therapy to patients with HoFH. Overall, Q2 2024 was a strong quarter for Ultragenyx. As expected, the second quarter bounced off the first quarter seasonality, leading to $147 million in total revenue. The broad strength across the commercial portfolio through the first six months of the year put us on a trajectory that gives us confidence we will exceed the guidance range that we established at the beginning of the year. With that, I'll turn the call to Howard to share more details on our financial results for the quarter and guidance for the year.
Howard Horn (CFO and EVP of Corporate Strategy)
Thanks, Eric, and good afternoon, everyone. I'll start by briefly summarizing our financials that were reported in our press release earlier today. As Eric noted, we reported $147 million in total revenue for the second quarter of 2024. Crysvita contributed $114 million, including $67 million from North America, $40 million from Latin America and Turkey, and $6 million from Europe. Dojolvi revenue in the second quarter was $19 million. Evkeeza revenue in the second quarter was $8 million, and Mepsevii revenue in the second quarter was $6 million. Our total operating expenses in the second quarter were $263 million, which included R&D expenses of $162 million, SG&A expenses of $81 million, and cost of sales of $21 million. Operating expenses included non-cash stock-based compensation of $39 million.
In the second quarter, net loss was $132 million, or $1.52 per share. As of June 30, 2024, we had $874 million in cash, cash equivalents, and marketable securities, which included net proceeds of $381 million from our offering in June. Net cash used in operations was $77 million for the second quarter and was $268 million in total for the first half of the year. As we discussed on our May call, there is seasonality in the first quarter because it includes items like the payment of annual bonuses. Our guidance for 2024 net cash used in operations remains unchanged and is expected to be less than $400 million for the year.
Shifting to revenue guidance, we are increasing our range for total revenue, which is now expected to be between $530 million and $550 million for the year. This reflects strong performance and trajectory across all of our products, including Crysvita globally and the launch of Evkeeza in our territories. Accordingly, we are targeting Crysvita revenue to be towards the upper end of our existing range of $375 million-$400 million, which includes all regions and all forms of Crysvita revenue to Ultragenyx. Specifically, it includes Crysvita product revenue from Latin America and Turkey, and cash and non-cash royalties from North America and Europe. We continue to expect Dojolvi revenue to be between $75 million and $80 million. With that, I'll turn the call to our CMO, Eric Crombez.
Eric Crombez (Chief Medical Officer)
Thank you, Howard, and good afternoon, everyone. The first half of the year has seen a number of important clinical catalysts for UX111 for the treatment of MPS IIIA. We announced data demonstrating clinically significant reductions in heparan sulfate that correlated with improved long-term cognitive function. This was followed up with our announcement in June that we reached agreement with the FDA that CSF heparan sulfate can be used as a surrogate endpoint for accelerated approval. We expect to finalize details of our filing package in a pre-BLA meeting later this year, with the goal of filing the BLA around the end of 2024.
For DTX401, for the treatment of GSD Ia, we announced positive top-line data from the phase III study that showed that treatment with DTX401 resulted in a statistically significant reduction in daily cornstarch intake at week 48, with maintenance of strong glucose control. Results from this study will be discussed with regulatory authorities in a pre-BLA meeting in the second half of 2024. For UX143, for the treatment of osteogenesis imperfecta, we announced 14-month data from the phase II portion of Orbit that showed treatment with resulted in a sustained 67% reduction in annualized fracture rate and persistent median annualized fracture rate of zero. There were also continued substantial improvements in bone mineral density, with a mean increase from baseline of 22% and a mean improvement in Z-score of 1.25.
For GTX-102, for the treatment of Angelman syndrome, in April, we shared additional phase I/II data from the expansion cohorts that showed rapid and clinically meaningful improvements across multiple domains. These improvements were consistent or exceeding those of the dose escalation cohort data at Day 170. We also shared that additional long-term data in dose escalation cohorts showed increasing and sustained clinical benefit through Day 758. There's been a lot of news flow in the space recently, and we feel very good about the ability of GTX-102 to improve the lives of patients affected by this disorder. We continue to see the patients in the phase II portion of the study developing new skills across multiple domains with no new serious adverse events, and we believe we are in a strong position as we advance phase III startup activities.
Last month, we completed a successful end-of-phase II meeting with the FDA, where we aligned on the design for a global 48-week, blinded, randomized, sham-controlled phase III study. We expect to enroll approximately 120 patients between 4 and 17 years of age, who have a full UBE3A deletion. The primary endpoint will be improvement in cognition, assessed by Bayley-4 cognitive raw score. The study will also include a key secondary endpoint of a multi-domain responder index, evaluating cognition, receptive communication, behavior, gross motor, and sleep. Individual secondary endpoints were also discussed and aligned on with the FDA for the domains of communication, behavior, motor function, and sleep. phase III study startup activities have been ongoing for some time, and now with FDA alignment, we are focused on initiating the study by year-end.
The ongoing phase II study includes 25 sites across 8 countries, which allowed us to respond to the significant global demand to participate in the study and for these sites to gain experience with GTX-102. With startup activities already in progress and alignment with FDA in design, we are on track to begin enrollment of our phase III study by the end of this year. While this initial phase III study will focus on patients with full deletions, who represent the majority of patients with Angelman syndrome, we are also planning to initiate an open-label study to evaluate GTX-102 for the treatment of patients with other genotypes and in other age groups in 2025. We expect to enroll both studies in parallel and plan to include both sets of data in a future BLA application. I'll now turn the call back to Emil to provide some closing remarks.
Emil Kakkis (CEO and President)
Thank you, Eric. In the first part of the year, we've made significant progress advancing our clinical pipeline, and we've performed well globally on the commercialization of four products. I'll close quickly by summarizing our key clinical catalysts for the rest of the year. For GTX-102 for Angelman syndrome, we're working to initiate the phase III study by the end of the year, and over time, plan to share updates on how the phase II patients are doing as they continue receiving maintenance doses. Our long-term data is far superior to any other data presented on ASOs or Angelman to date, and this puts us in excellent position for the future of that program. For the phase III portion of the UX143 ORBIT study, there are two interim analyses planned, with the first anticipated by year-end or early 2025.
The first analysis will have a stringent threshold of P value less than or equal to 0.001. If the threshold is not met, a second interim analysis will occur a few months later, followed by a final analysis at 18 months. The first interim analysis will not be reported to the company by the Data Monitoring Committee unless the data have met this very stringent threshold. It is important for study integrity that we run these analyses very carefully and rigorously. In the event of an interim analysis that clears the threshold, we would share that outcome, but top-line results would not be announced immediately, as the study would require patients to complete their final visits over a couple of months, and then there's time to collect and prepare the data for a formal analysis.
For UX701 for Wilson disease, we expect to share Stage one data in the second half of the year. In this dose-finding stage, a data readout will be prompted once the last patient in Cohort 3 has been on therapy for six months or more, followed by some additional time to collect and analyze all of the data. All of these are very exciting catalysts, and while the teams are executing on these clinical programs, we will also be working on two BLA submissions, one for UX111 for Sanfilippo syndrome, which is expected around the end of the year, and the other for DTX401 for glycogen storage disease type Ia, which is expected in 2025. Ultragenyx is at an incredible inflection point.
Over the next 12-18 months, we expect to have filed 2 BLAs, provide phase III data on UX143, and should be well on our way with the GTX-102 phase III study. All the while, we are generating meaningful revenue growth, which is now expected to be between $530 million and $550 million this year. With that, let's move on to your questions. Operator, please provide the Q&A instructions.
Operator (participant)
Thank you very much, sir. At this time, we will be conducting a question and answer session. If you would like to ask a question today, please press star then one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. Press star and then two, if you would like to remove yourself from the question queue. Participants are limited to one question and one follow-up at a time. The first question that we have comes from Gena Wang of Barclays. Please go.
Gena Wang (Managing Director of Biotech Equity Research)
... Angelman syndrome, data update. We also saw quite a few other, data update from both Ionis and Roche. Maybe, I mean, what is your latest thoughts, you know, regarding the competitive landscape and the, the read-through to your trial design, especially if we're looking at the loading dose frequency and also the endpoints, such as expressive communication for Bayley?
Joshua Higa (Head of Investor Relations)
Emil, is your line muted? We can't hear you. All right, looks like we're having maybe a little bit of technical difficulty, and we've lost Emil's line. Eric, are you able to to help out with that question?
Eric Crombez (Chief Medical Officer)
Yep, thanks. Certainly, we've been following along the important data updates that were released around the time of ASO. So certainly feel very good about where we stand, looking more closely at the data, both from Roche and importantly, from Ionis. We, as we've mentioned, we had a very successful end of phase two meeting with the FDA, and we really have locked in our plans for phase three as we're looking forward to first patient and by end of year. We have done some thought on loading dose and reducing from four to three loading doses, which also gives us the ability to increase our dose and drive to higher doses in a shorter period and really get to, you know, a data readout for that phase three under one year of time.
Again, you know, looking across all of the important domains we've been talking about collectively in the MDRI and individually as secondary endpoints, we're seeing great movement across all of those domains. We are moving forward with cognition raw scores for our primary endpoint, but certainly looking at expressive communication as an important secondary endpoint.
Emil Kakkis (CEO and President)
Hello, I'm back.
Joshua Higa (Head of Investor Relations)
Yeah, Eric took care of the call. Gina, was there any follow-up there that you had for Emil?
Gena Wang (Managing Director of Biotech Equity Research)
Sure. Yeah. So maybe regarding the Wilson data in second half this year, maybe, you know, how many more patients and what kind of data beyond biomarker you will share with us?
Emil Kakkis (CEO and President)
Well, there's a total of 15 patients, five in each cohort, so it'll be 15 patients worth of data, five at each dose level. It'll be primarily biochemical. There's not enough patients in there to have a lot of clinical information, right, that you could... You know, so it'll be focused on copper, copper levels, distribution levels, and other aspects of copper metabolism. I think will give us an understanding of, is the gene therapy working well? We had certainly an early indication, and that was very encouraging. So it'll primarily focus on the biochemical part of the story at this point.
Gena Wang (Managing Director of Biotech Equity Research)
Great. Thank you.
Operator (participant)
Question we have comes from Salveen Richter of Goldman Sachs. Please go ahead.
Joshua Higa (Head of Investor Relations)
Hey, Salveen, I'm not sure. Is your line muted? We can't, we can-
Salveen Richter (Managing Director of Global Investment Research)
Hi, can you hear me now?
Joshua Higa (Head of Investor Relations)
Loud and clear, Salveen. Go ahead.
Salveen Richter (Managing Director of Global Investment Research)
Oh, so sorry about that. Thank you for taking my question. Could you help us understand how you look at OI with regard to the phase two data translating to phase three here, and particularly as these patients see improvements, how that kind of impacts, you know, the rate of fractures here for the population, and your assumptions around that in the phase three trial?
Emil Kakkis (CEO and President)
Well, I think what we've shown at the 14-month data was, in fact, that the bone mineral density continues to increase dramatically, and the p-value got much smaller. So remember, that's looking at all the patients, not just the median. That tells you the p-value declining substantially tells you that all the patients are moving toward a reduction in fractures. So we feel the effect, the effect is very large. In terms of translating to phase III, we know from the data we had in a few placebos that they do not see bone mineral density improvement during this period of time, so there will be no placebo effect from that. With regard to fractures, fractures are dependent on both disease severity and also environmental factors, like what the patient's doing.
Our expectation is that patients, when they feel better, could start doing more work, but what we have seen is patients that have gotten stronger and been on treatment for a longer period of time will have falls and not have fractures. So we feel pretty confident that the strength of bones is such to even compensate for any change might occur because patients are more active. But we do think that the way patients feel their activity will bode well for supportive clinical data and how the patients are doing, which I think will support the value of the product and its clinical meaningfulness. Did I hit on the thing you were most interested in, Salveen?
Salveen Richter (Managing Director of Global Investment Research)
That's really helpful. Thank you.
Operator (participant)
The next question we have comes from Dae Gon Ha from Stifel. Please go ahead.
Dae Gon Ha (Director of Biotechnology Equity Research)
Hey, good afternoon, guys. Thanks for taking my questions. Hope I'm coming off okay. Can you guys hear me?
Emil Kakkis (CEO and President)
Loud and clear, Dae Gon.
Eric Crombez (Chief Medical Officer)
We do.
Dae Gon Ha (Director of Biotechnology Equity Research)
Awesome. So maybe just revisiting or maybe rewording Gena's earlier question, Emil, coming out of that, ASF, and we certainly have some details around the, the different domains and its impact by the ASOs. I guess, now that the phase three trial design is set, is there a certain strategy you have in terms of maximizing GTX-102's product differentiation as you feel about, the other ASO coming through, fairly quickly? And then just maybe a little bit, tangential here, but I was wondering if you guys ever thought about using an Ommaya reservoir for GTX-102, just thinking about intrathecal administration and its affiliated, side effects. I mean, would an Ommaya reservoir be like a lifecycle management strategy where you can get more drug, a bit more safely, perhaps, with greater potency? Thanks so much.
Emil Kakkis (CEO and President)
Thanks, Dae Gon. So on the first, I think the thing that's most important about looking at our data is that we actually are showing long-term data and showing the Bayley-IV cognition into the double digit range for the majority of patients, if you look long enough. So we were showing, you know, two years plus of data. I haven't seen any of that from anyone. So for right now, we're the only program that's showing that kind of data. Our drug is more potent than the other drugs. We're operating in the 5-14 milligram range, far below that. That tells you the science of what we've been talking about is right. The targeted region that we have padded is more potent and more effective, so we believe we'll differentiate on superior efficacy.
I'm waiting to see other data from people that will actually match what we have. With regard to your point, I think it's a good point. I think one of our philosophies in Rare Pearls is that we first make things work, and then we make them easy. Our goal is to get a drug, approved drug, for this Angelman syndrome as soon as possible. But then we'll look at how do you make this easier for patients or more potent. An Ommaya is one thing. It is certainly an invasive approach. It has its upsides and downsides. There are also some companies that make lumbar catheter-type devices, which would have catheters inside, which you could access, which is a much simpler procedure than a lumbar puncture through a port, a similar idea. So certainly those are things we can do as a lifecycle management.
Those are things we will consider, and we as a company never sit still. If we get approved, we're still gonna be constantly looking to ways to improve the patient experience, improve the efficacy, and continue to drive forward with the best possible outcome. So we feel like we're in great position. And after ASF, I haven't seen anything that tells me any differently.
Dae Gon Ha (Director of Biotechnology Equity Research)
Fair enough. Thank you very much, and congrats on the progress.
Emil Kakkis (CEO and President)
Thanks.
Operator (participant)
Thank you. The next question we have comes from Tazeen Ahmad of Bank of America. Please go ahead.
Tazeen Ahmad (Analyst)
Hi, good afternoon. Thanks for taking my question. On Wilson, you're talking about doing that interim stage one readout, and maybe, Emil, I wanted to get a sense on, initially, your thought was that you would have a readout on the first half, and then it's moved, a couple of times to now second half of the year. Just curious, the reason for the delay. And then once we do see that data, what should we expect as next steps in the development of that program? Thanks.
Emil Kakkis (CEO and President)
Yeah. So, Tazeen, thank you for the question. I think one of the first things is that to finish out the cohort 3 took longer. We ended up having a patient that qualified and something happened, and we had to... It ended up dragging out the last patient, and so that was part of one of the problems. One thing we saw in the cohort 1 data that we did put out is that it actually took more time. It took more than six months to see the effects of the drug. It's a transporter for copper. It's not gonna behave like some of our enzymes, so we're learning a little about it. So our take was we need to go at least 6 months of data from the last patient in, and that's what the timing is.
You have to add on to that time to clean the data. It is an international phase II/III study, prepare the analyses and put it out. So we felt it's important to get this right and make good decisions, and so that's where it is. But, we're encouraged by the early data we saw, and I think there is a gene therapy treatment for Wilson on the horizon, and we'll continue to put that data forth and come up with our, our plan for the... Heading into phase III. Thanks, operator. Next question, please.
Operator (participant)
Thank you. So the next question we have comes from Kristen Kluska of Cantor Fitzgerald. Please go ahead.
Kristen Kluska (Managing Director and Biotechnology Equity Research Analyst)
Hi, congrats on a great quarter. On setrusumab, I wanted to ask if you think that there are any benefits this drug could potentially show as it relates to the pain these patients experience. Is there reason to think that both reducing those fractures and putting down better bones has the potential to have an impact on pain?
Emil Kakkis (CEO and President)
... Yes, our impression from the phase II patients, particularly with their increased activity, they're feeling better, they're having less pain. And while we love to talk about fractures all the time, OI patients have weak bones, and what that means is lots of microfractures. So if they do some strong activity, they'll feel terrible the next day because they've probably induced a bunch of microfractures. So it's not a single point fracture. What we can see from the patients treated at the one-year point or beyond, patients having much more activity, not needing wheelchairs, not being as afraid of physical activity. So we have confidence that stronger bones will reduce microfractures and will improve pain.
We are evaluating both pain, quality of life and other measures in the study, and it's a large enough study that should help us power those endpoints. So we think, it's one of the ways that we'll make, I think, setrusumab a really important therapy for OI.
Kristen Kluska (Managing Director and Biotechnology Equity Research Analyst)
And then just on that point, I know people sometimes ask if you're feeling better and you're doing more activities, does that open the door for any potential fracture risk? But maybe on the other end of that spectrum, if people are exercising and doing more activity, could that help even further slow down any type of bone loss or density loss? Thank you again.
Emil Kakkis (CEO and President)
Yeah, actually, it's a very good point. I think you certainly could increase fracture risk. We did have a patient who started doing sports again and did have a fracture, but I'm not the one to tell a patient, "You feel great now. Now, don't do anything with that," right? It's just not rational to think that. What I will say is, these patients, if you're sedentary, you or I sit in our bed and we don't do enough, our bones get weaker. So the exercise they do will, will actually stimulate their bones to lay down the bone. Where their bone is weakest, it'll actually enhance their bone strength further. So I think it'll have a beneficial effect for them to be more active and with sports or anything else. So we're not worried about the overall risk of getting more fractures.
We think it's part of a healthy pattern toward more activity, stronger bones, and better lives for these OI patients.
Kristen Kluska (Managing Director and Biotechnology Equity Research Analyst)
Thanks, Emil.
Operator (participant)
Thank you. The next question we have comes from Anupam Rama of JP Morgan. Please go ahead.
Speaker 19
Hi, everyone. This is Priyanka on for Anupam. Just a quick question from us. For UX111, even though the BLA filing will be based on available data, are there any gating factors for the BLA filing later this year or into early next year?
Emil Kakkis (CEO and President)
Well, the one thing we need to make sure is that the CMC put together with our contract manufacturer, they're doing an excellent job. This is Andelyn. They're derived from the Nationwide Children's people. They know their stuff. They do a good work. And so we feel we're pretty much on track to get where we need to go. That would be one thing that has to be in line. We're having our discussion with the agency about exactly what needs to be in a BLA, and the agency has shown the proper flexibility on what needs to be now, what can be in later. And I think, right now, I don't see any gating factors. It is a lot of work putting a BLA together and, but we're expected to get there this year.
Speaker 19
Thanks so much for taking our question.
Joshua Higa (Head of Investor Relations)
Operator, next question, please.
Operator (participant)
Thank you. The next question we have comes from Joon Lee of Truist Securities. Please go ahead.
Joon Lee (Managing Director and Biotech Analyst)
Hey, congrats on the strong quarter, and thanks for taking our question. During Biogen's conference call this morning, when asked why they did not opt into Ionis' Angelman program, Biogen implied that the data may not have crossed the preset go, no-go threshold. Knowing what you know about the competing ASO from what's been publicly disclosed, in what ways do you think GTX-102 may be a better option for patients than Ionis study two? In other words, as patients consider enrolling for either GTX-102 or Ionis study, what would be the selling point for your program? Thank you.
Emil Kakkis (CEO and President)
Well, I think I am sure Biogen's considering looking at all the data that are publicly available since we show substantially higher levels of Bayley-IV condition achievement over longer periods of time and steady growth and in multiple domains. In fact, I think that's a strong data set. What we've seen from our Ionis competitor is a limited amount of data through six months. So I'm sure that Biogen has the capability to understand what the data look like and how to compare, and they made their choice. It seems unlikely to me that they wouldn't have opted in if they had a product that was equal to ours, and with this point, we don't think it is equal. And I think our data, longer term, is substantially stronger, and it didn't meet their criteria and might not have met ours if we were doing their product.
But right now, we feel good about our product, its potency, and the fact that I think it's the number one ASO for Angelman at this point.
Joon Lee (Managing Director and Biotech Analyst)
Thank you.
Operator (participant)
Thank you. The next question we have comes from Maury Raycroft of Jefferies. Please go ahead.
Maury Raycroft (Equity Research Analyst of Biotechnology)
Hi, thanks for taking my question, and I'll ask one about Wilson's disease. For your upcoming update, you're assessing global copper metabolism by biomarkers. What would be considered a win or what magnitude of change do you need to see to advance to phase III, or what scenarios could require further optimization?
Emil Kakkis (CEO and President)
Thanks, Maury. With Wilson, to have an effective gene therapy, I think it's necessary to see patients be able to get off standard of care, right? And maintain free copper levels and urinary copper excretion. That indicates that they are now detoxifying copper through the proper pathway, right? So first off, we have to be able to replace chelators as a way to detox copper. Secondly, we'd like to see some significant improvement in the majority of patients in copper distribution. That is, the ceruloplasmin copper levels, which are generally very low in these patients and are the source of copper to be distributed to the brain and other places. And in many patients, we think that copper deficiency is a contributor to the Wilson phenotype. So those are the two things we're looking for.
A substantial improvement in copper distribution over their background baseline, particularly in those patients where it's low, and the ability to remove standard of care and maintain toxicity control.
Maury Raycroft (Equity Research Analyst of Biotechnology)
Got it. That's helpful. Thanks for taking my question.
Operator (participant)
Thank you. The next question we have comes from Joseph, Joseph Schwartz of Leerink Partners. Please go ahead.
Joseph Schwartz (Managing Director and Senior Biotechnology Analyst)
Hi, all. This is Will on for Joe. Thanks for taking our question. Congrats on the progress this quarter. One for us on GTX-102. Outside of the study design and endpoints, just wondering if the FDA has provided any color on the bar success for approval. Along the same lines, can you remind us of our understanding of what a clinically meaningful benefit would be on the Bayley-IV endpoint? Thank you.
Emil Kakkis (CEO and President)
Well, first off, they agreed to a continuous variable analysis for the Bayley-IV, right? So there was no set threshold established or required. They felt that a continuous variable approach was the right way, so they didn't require responder analysis. We do a responder as part of the MDRI, which will support the clinical meaningfulness. So that's what they've required of us. They haven't set any numbers. In our mind, if we can show what we've already seen in phase II, which is achieving in majority of patients into the double-digit range of Bayley-IV, that's essentially twice what is considered a statistically significant improvement in the Bayley score. I think that's quite important. But I want to be clear about it.
While we picked Bayley-IV as a primary, the other endpoints are part of the story, and the value of it, as we see it through the MDRI, the eyes of the MDRI, is this combination of factors that is a change of life for patients. I'd look at the big picture. The Bayley-IV score itself doesn't tell the whole story. Knowing a patient sleeps well, is not falling down as much, the behavior is calmer, is understanding language, spoken language instructions better. These are all things that are a change of life for patients at home, and, and we think some of these patients have multiple domains of improvement are going to tell you why this drug would be important for patients. If we can replicate that in phase III, what we've already shown you in phase II, I think we're in good shape.
Operator (participant)
Thank you, sir. The next question we have comes from Yaron Werber of TD Cowen. Please go ahead.
Yaron Werber (Managing Director and Senior Sesearch Analyst)
Great, thanks for including us as well. Maybe I just have a one-on-one follow-up. Abel, maybe just on Angelman, the 48-week endpoint, can you give us a little bit of a sense what kind of a delta in terms of powering are you kind of hoping to see and planning to see in the phase III? And is there gonna be a longer look as a secondary endpoint? And then just on GSDIa, you know, we're beginning to get questions kind of how to think about what's feasible in terms of the commercial opportunity here. I think you've kind of talked about price being, let's say, just you know, in the mid sort of $1.1 million or so.
I don't want to speak for you, but how big of a market can we, can we think here? Thank you.
Emil Kakkis (CEO and President)
Great. So the 48-week data, we actually, if you look at our April AAN, the Academy of Neurology, deck, we actually put a slide on powering in there, showing we're well above 90th percentile. Even if you assume the placebo group had three times the natural history or three or four times the natural history, we still had well more than 90% power. In fact, with the typical natural history control group, we would be well above 95% power. So it is very well powered to see the effect sizes we're seeing right now, which we're into the double-digit range, in when you talk about 48 weeks. One of the reasons we've been longer is we felt you accumulate more improvements, and that made it a better story overall. So that's with the powering on Angelman.
With regard to GSDIa commercial opportunity, I think the thing to recognize is, for the patients, the exact amount of cornstarch is less the issue than the fear of dying if they miss their doses, the brittle nature of their disease. What we're seeing with these patients is a change in their outlook on what's happening to them because they are no longer highly dependent on cornstarch to survive. We think our data in the phase III, because of the blinding and the inability to tell patients and doctors what their sugars were, didn't get us as strong a reduction as we've seen, and we are seeing an extension, but we know that number will get better and better as their physiology changes. The effect of feeling better and having a change of life is very much there.
We think there's a high urgency in this disease. I think people hate living with a gun to the head, waiting to die, and the corn starch is just a representation of that risk that occurs for them every day... And it's nothing like some of the other diseases, with regard to the urgency that exists. So we think it will be highly desired in, in the patient population, and we expect patients to want to get dose. And we think that's the key to gene therapy success commercially has been, what's the level of patient urgency? That's been defining what's been happening. With regard to pricing, we certainly have not put out pricing at this point. It's, it's a bit too early. We have said in the past that pricing in the $1 million-$2 million range is possible.
I think price points have gotten even higher for some programs, but we haven't sat down what our plan is. We're gonna look carefully at this and come at it. But I think GSDIa is a very reasonable and important opportunity. I think it will do well, and I think it'll be an important new therapy. I expect it to perform more like some of the other programs where there's high levels of urgency.
Operator (participant)
Thank you, sir. The next question we have comes from Jeffrey Hung of Morgan Stanley. Please go ahead.
Michael Riad (Analyst)
Hi, this is Michael Riad. I'm for Jeffrey Hung. Thank you for taking our question. Going back to setrusumab and thinking about that cycle of fractures leading to bone deformation and then loss of activity, what factors do you think play a bigger role in the treatment course? Is it age or OI type? I mean, if you think about, like, the profile of setrusumab, do you view it as, like, a broadly better option for most pediatric patients, regardless of type, whereas for adults, you'd expect more OI type-dependent penetration? Thank you.
Emil Kakkis (CEO and President)
Well, you know, I think each patient is gonna have a reason to be treated. It may be different. If you're a Type three patient or Type four with a really severe bone disease, and you're treated when you're one or two years old, our hope, and we will see what the phase III data show, is that we could be transformed in terms of stopping fractures, stopping vertebral compression, and not basically destroying your skeleton before you're 3 or 4 years of age and ending up in a wheelchair. So that would be what you could do when you're treating kids very young. However, when they're old, like, even if you're in a wheelchair because you have deformed bones, you're still fracturing, you're still in pain all the time.
Being able to stop being in pain by stopping fracturing, even if you can't change deformation, is still highly valuable in an adult with Type three or four. For Type one, probably the severe half of that population will have enough fractures where at any age, young or old, it's gonna be beneficial. They don't have as much deformation, but being able to be comfortable participating in sports or activities you might not have been doing before, I think will, will get Type one's treated. There may be some Type one's who are milder, don't have as many fractures, and there might not be as an addressable, as much addressable need in those patients, so we wouldn't expect all Type one's. What I can say from the data we've shown you, though, the Type one's do really well on the treatment, as do the Type three's and four's.
We expect that we'd have a good penetration of all three types as well as in all ages, because we think there's a reason to treat at any point in life with any of these diseases.
Michael Riad (Analyst)
Thank you. I appreciate that added color. And then, for Angelman, I just wanted to circle back to something. So obviously we saw, like, competitor data that showed good responses up to six months, and the phase III is out to 48 weeks, but that makes the phase I, II, giving a bit of a more unique insight into the longer term benefits. So I was just wondering how that data, like, you think it can be used for evaluating that more, like, durable clinical aspect and like, the developmental gains that have been achieved?
Emil Kakkis (CEO and President)
Are you asking about our data or someone else's data? I didn't quite understand.
Michael Riad (Analyst)
I'm asking about, like, the phase I/II, like, how the, that phase I/II data, especially, like the-
Emil Kakkis (CEO and President)
Our data.
Michael Riad (Analyst)
longer-term data can... Yes.
Emil Kakkis (CEO and President)
Yeah. Well, I think what's important about the long-term data is to see patients continue to gain ground. They don't plateau, they continue to gain ground, which tells you that 48 weeks is only one point on a longer journey where these kids are going. Where they can go is still unclear. How much better could they get? The other point I would make is that while you get a brain to start functioning better, it does take time for kids to learn things, right? Just like growing up, you had, took time to learn them, right? So there's a developmental component, particularly in receptive communication and expressive communication, that we think might take more time, as kids have to essentially learn something that they didn't know and they can't understand.
So those complex developmental functions might take more time, but we feel that 48 weeks is a good time point to capture enough improvement, to shift, to demonstrate the shift from the control group, get the drug approved. But the long-term and continued improvement will be why patients stay on drug and why the product will penetrate the population if successful in phase III.
Michael Riad (Analyst)
Thanks so much for answering our question.
Operator (participant)
Thank you. The next question we have comes from Jack Allen of Baird. Please go ahead.
Jack Allen (Research Analyst covering Biotechnology)
Great. Thanks so much for taking the question, and congratulations on the progress over the quarter. I wanted to ask on setrusumab. I guess a few little parts to this question. The first of which I was wondering what we should expect as we look towards the second half of the year and the presentation of additional data for setrusumab. It looks like the BMD and Z-scores are continuing to improve over time. Do you expect to provide additional color as it relates to differences in fracture rates over time with setrusumab and how that correlates with the biomarkers we're looking at there? And then I also just wanted to follow up and ask about any comments as it relates to that enrollment in the ORBIT study and the types of patients you're seeing in that trial versus the phase two portion of that study.
Emil Kakkis (CEO and President)
... Sure. So with regard to the second half, we haven't set on a plan now, a particular set of data that we might present or not. I mean, honestly, right now, our goal is to crank phase III and to be prepared as necessary to file a BLA if we're able to hit an interim. But I, right now, I'm not sure if we will put out more data, but the patients clearly have continued improvement over time, and 14 months is certainly not the end of the story. They continue. The patients have been on the 17-24 months, have continued to do extremely well and are—it's very encouraging and it's been transformative. So we definitely think that's true.
We may put it out at some point in time, but I think most people, our eyes are already turned toward interim analyses in 2025, so we haven't committed to other more data yet. With regard to the ORBIT type of patients, we did enroll more type three's and four's. We now put up the ratio, but in the first phase II study, we had 17 type one's and seven type three's and four's. And it's a significantly larger type three's and four's in the ORBIT study, which is what we wanted. We wanted to get more severe patients that had more fractures, that had more medical need, and we were able to enroll a lot number of those. I think actually the phase II data stimulated them to get involved because before they were apprehensive.
Once they saw data, then the doctors started putting in the patients in most need. So there is a little bit of shift there, but I don't think it'll be substantially different in what we see compared to our phase II data.
Jack Allen (Research Analyst covering Biotechnology)
Got it. Thanks so much for that context. Maybe just one brief follow-up. I know you get a lot of questions on how to think about the powering of the Orbit study, but in that context, what were your expectations for enrollment when you set out to enroll the phase III portion of Orbit? And I guess, did you enroll potentially more severe patients than expected? Any thoughts on how that may impact the power?
Emil Kakkis (CEO and President)
Well, we originally started with a 195-patient study, and then when we saw our first look of data at 6 months, it was pretty clear that the fracture reduction of 67% is way past what's needed. We brought that down to 150, which is not a huge difference in power, frankly, but we wanted to keep it at that large because there's... You want to get enough type ones, type threes and fours to look at the subsets, right? And you also had peds and adults, right? So you have to look at the age subsets, right? So the number 150, you could look at as the overall powering, but I also look at it as having enough of each group to be able to look at their data and understand the benefit in young or old, or type threes, fours, or ones.
So that was one of the drivers in maintaining the number 150. I think with the fracture reduction rate and assuming a higher fraction rate in the study, you know, there was plenty of power. We could have made the study smaller, but I think when you try to cover the types and the severities, and the age groups, what we put, I think, was a good design that will capture the amount of data across all, all types of OI.
Jack Allen (Research Analyst covering Biotechnology)
Got it. Thanks so much for the color, and congrats on all the progress.
Emil Kakkis (CEO and President)
Thank you.
Operator (participant)
Thank you. The next question we have comes from Lisa Walter of RBC. Please go ahead.
Lisa Walter (VP Biotech Equity Research)
Oh, great. Thanks for taking our question. This is Lisa on for Luca. This question is for Emil. More of a big picture question. Wondering if we can get your thoughts on the future of the rare pediatric disease voucher program. It sounds like this is set to expire on September 13, unless it is reauthorized by Congress. So if it's not reauthorized, how might this affect rare disease drug development going forward? Any color there would be much appreciated. Thanks so much.
Emil Kakkis (CEO and President)
Yes. So the sunsetting of being able to get them to be able to apply for new ones is happening later this year and through next year. For us, as a company, there should be two PRVs available to us for if we file for UX111 and DTX401, we should be able to get two. So for us, it doesn't affect us in the short term, in our own financial planning. In the long run, the PRV vouchers really change the equation on what happens in some of the ultra-rare diseases. And for us, we've sold two vouchers, something like $170-$180 million of additional cash for Ultragenyx. This had a major impact on our ability to develop other rare disease drugs. We've submitted that information. We're highly supportive of the PRV.
We think there's bipartisan support on the Hill, and there's rarely that for almost anything. So right now I feel that it will get done, but, you know, it hasn't happened yet, and election year is a crazy time to do things, but we think it's something that, you know, rare doesn't, doesn't matter with regard to what party you are, if you have a rare disease. So we, we hope the PRV will get the support. We are certainly providing it. Thanks, operator.
Lisa Walter (VP Biotech Equity Research)
Thank you.
Emil Kakkis (CEO and President)
Can we go to the next question?
Operator (participant)
The next question we have comes from Liisa Bayko of Evercore ISI. Please go ahead.
Liisa Bayko (Managing Director)
Hi, this is Sreeni for Lisa. Thanks so much for taking our questions. So, we noticed that Amgen is running an open label phase III study for Romosozumab in OI, and they have indicated that if the phase III study is positive, they may have an opportunity to pursue approval and launch in the OI. So we're just wondering, what implications do you think it would have for setrusumab if Amgen decides to pursue approval in OI? Thank you.
Emil Kakkis (CEO and President)
... Hi. Well, that's news to us. They've already given us the intellectual property access, so I don't think they've had that much interest in it. They, as a biologic for them, osteoporosis is a huge indication. It's growing. There's a big shift toward anabolic agents in osteoporosis. I really think that's their focus. With regard to OI, we've seen their phase II data. We understand their dosing from the published comments in the ClinicalTrials.gov or the European version of it. Right now, they're getting substantially less bone mineral density at the dose levels they're using. So we're a superior treatment in terms of our bone mineral density improvement, and we will then be superior in our fracture reduction. So I think you should look at this as an unclear story.
What they've done in their phase III is not optimize the drug nor the presentation for OI. So I really don't have concerns right now because we know our data looks far superior. For them to get to our data, they would have to change their dosing dramatically from phase III, which is not likely to happen at this point. So at this point, I think they will be inferior to us, and I think that will be a factor. Now, could they use a higher dose of romo? Potentially, but then the differentiation regard to pricing goes away if you have to give five times or eight times more drug to match our dosing level. So we feel like we're in a good position, and I haven't heard anything from Amgen about this before.
I believe that the osteoporosis is in their main space, for it, and hasn't been listed as part of their rare disease franchise at all. So I'd be surprised if they're changing that.
Liisa Bayko (Managing Director)
That's helpful. Thank you.
Operator (participant)
Thank you. Ladies and gentlemen, we have reached the end of our question and answer session, and I would like to turn the call back to Joshua Higa for closing remarks. Please go ahead, sir.
Joshua Higa (Head of Investor Relations)
Thank you. This concludes today's call. If there are additional questions, please contact us by phone or at [email protected]. Thank you for joining us.
Operator (participant)
Thank you. Ladies and gentlemen, that then concludes today's conference. Thank you for joining us. You may now disconnect your lines.
