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spk18: 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.
spk03: Thank you. We have issued a press release detailing our financial results, which you can find on our website at Ultragenyx.com. Joining me on this call are Emil Kakas, Chief Executive Officer and President, Eric Harris, Chief Commercial Officer, Howard Horn, Chief Financial Officer, and Eric Krambes, 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.
spk16: 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 earlier this year on both UX111 in San Filippo Syndrome and GTX102 in Angelman Syndrome, We recently announced positive phase three results from the DTX401 gene therapy for the treatment of patients with glycogen storage disease type 1A and additional long-term positive phase two 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 two meeting with the FDA where we aligned on phase three study design and key endpoints to be evaluated. Our teams have been working with our study sites to initiate our global phase three study by the end of this year. On UX111 for Sanfilippo syndrome type A, we also reached agreement with AHC on a path forward to seek accelerated approval. The FDA has agreed that cerebral spinal fluid heparin 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 6 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 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, Eric 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.
spk13: Thank you, Emil, and good afternoon, everyone. I'll start with Chris Vita's performance in the United States. The demand for Chris Vita in the U.S. remained strong in Q2 2024. Approximately 60% of the stock 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 CRISPR 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 CRISPR in Latin America where we lead commercialization, our LATAM team delivered another successful quarter by adding approximately 60 new patients to CRISPR. 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 DiGiovi, growth of new start forms remains strong. In the US, 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 continue to grow, adding approximately 10 new prescribers in Q2 2024, with half of them writing more than one prescription. For DiGiovi across Europe and the MENA region, revenue is currently driven by named patient sales requests. There are approximately 215 patients treated under MPS 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 KISA. In the EMEA region, we added approximately 60 new patients in the second quarter who were being treated through MPS 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 FKESA as a treatment option. We expect demand for FKESA 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.
spk01: 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. Prospita contributed $114 million, including $67 million from North America, $40 million from Latin America and Turkey, and $6 million from Europe. The Jolvi revenue in the second quarter was $19 million, Efkiza revenue in the second quarter was $8 million, and Metsevi 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 use and 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 and $550 million for the year. This reflects strong performance and trajectory across all of our products, including Prospita globally and the launch of Ifkiza in our territories. Accordingly, we are targeting Prospita revenue to be towards the upper end of our existing range of $375 million to $400 million, which includes all regions and all forms of Prospita revenue to Ultragenyx. Specifically, it includes Crespita product revenue from Latin America and Turkey and cash and non-cash royalties from North America and Europe. We continue to expect the Jolby revenue to be between $75 and $80 million. With that, I'll turn the call to our CMO, Eric Prondos.
spk11: 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 MPS3A. We announced data demonstrating clinically significant reductions in heparin 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 heparin 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 GSD1A, we announced positive top line data from the phase three 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 the 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 two portion of ORBIT that showed treatment with citruzumab 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 GTX102, for the treatment of Angelman syndrome, in April, we shared additional Phase 1-2 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 benefits through day 758. There's been a lot of news flow in the space recently, and we feel very good about the ability of GTX102 to improve the lives of patients affected by this disorder. We continue to see the patients in the phase two 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 three startup activities. Last month, we completed a successful end of phase two meeting with the FDA where we aligned on the design for a global 48-week blinded randomized sham-controlled phase three 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 for 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 three 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 two study includes 25 states across eight countries, which allowed us to respond to the significant global demand to participate in the study and for these sites to gain experience with GTX102. With startup activities already in progress and alignment with FDA design, we are on track to begin enrollment of our phase three study by the end of this year. While this initial phase three 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 GTX102 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.
spk16: Thank you, Eric. In the first part of the year, we've made significant progress advancing our clinical pipeline. We've formed well globally on the commercialization of poor products. I'll close quickly by summarizing our key clinical catalysts for the rest of the year. For GTX102 for Angelman syndrome, we're working to initiate the phase three study by the end of the year, and over time, plan to share updates on how the phase two patients are doing as they continue receiving maintenance doses. Our long-term data, is far superior to any other data presented on ASO's arrangement to date, and this puts us in excellent position for the future of that program. For the phase three 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 .001. If the threshold's 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 steady integrity to 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 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 cohort three 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 collection and storage disease type 1A, which is expected in 2025. Ultragenics is at an incredible inflection point Over the next 12 to 18 months, we expect to have filed two BLAs, provide phase three data on UX 143, and should be well on our way to put the GTX 102 phase three study. All the while, we're generating meaningful revenue growth that's now expected to be between 530 and 550 million this year. With that, let's move on to your questions. Operator, please provide the Q&A instructions.
spk18: 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 1 on your telephone keypad. A confirmation tone will indicate your line is in the question queue. Press star and then 2 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 Gina Wang of Barclays. Please go ahead.
spk04: Angelman syndrome data update. We also saw quite a few other data updates from both Ionis and Roche. Emil, what is your latest thoughts regarding the competitive landscape and 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?
spk03: 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 help out with that question?
spk11: Yep, thanks. And certainly we've been following along the important data updates that were released around the time of ASF. So certainly feel very good about where we stand looking more closely at the data both from Roche and importantly from IONIS. 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.
spk16: Hello, I'm back.
spk03: Yeah, Eric took care of the call. Gina, was there any follow-up there that you had for Emil?
spk04: 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 would share with us?
spk16: 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 data. 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 levels, distribution levels, and other aspects of copper metabolism. I think it 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.
spk04: Great. Thank you.
spk18: The next question we have comes from Salveen Richto of Goldman Sachs. Please go ahead.
spk03: Hey, Salveen. I'm not sure. Is your line muted? Hi.
spk17: Can you hear me now?
spk03: Loud and clear, Salveen. Go ahead.
spk17: 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 II data translating to Phase III 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 III trial?
spk16: Well, I think what we've shown at the 14-month data was, in fact, that the bone marrow 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 is very large. In terms of translating to phase three, we We know from the data we had on a few placebos that they do not see bone marrow 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 the bones is such to even compensate for any change that might occur because patients are more active. But we do think that the way patients feel and their activity will bode well for support of clinical data and how the patients are doing, which I think will support the value of the product and its clinical mean for this. Did I hit on the thing you were most interested in telling me?
spk17: That's really helpful. Thank you.
spk18: The next question we have comes from Dagon Ha from Stifle. Please go ahead.
spk14: Hey, good afternoon, guys. Thanks for taking my questions. Hope I'm coming off okay. Can you guys hear me?
spk03: Loud and clear, Dagon.
spk14: Awesome. So maybe just revisiting or maybe rewording Gina's earlier question, Emil, coming out of that ASF, and we certainly have some details around 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 Omaya reservoir for GTX 102, just thinking about intrathecal administration and its affiliated side effects, I mean, would an Omaya reservoir be like a lifecycle management strategy where you can get more drug a bit more safely, perhaps, with greater potency? Thanks so much.
spk16: Thanks, Dagon. 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-4 cognition into the double-digit range for the majority of patients if you look long enough. So we were showing 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 to 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 and 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's Syndrome as soon as possible. But then we'll look at how do you make this easier for patients or more potent But OMAIA is one thing. It is certainly an invasive approach. It has its upsides and downsides. There are also companies that make lumbar catheter-type devices, which would have catheters inside, which you can access with 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 going to 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 a great position. And after ASF, I haven't seen anything that tells me any different way.
spk14: Fair enough. Thank you very much, and congrats on the progress.
spk18: Thank you. The next question we have comes from Tazeen Ahmed of Bank of America. Please go ahead.
spk09: 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 times to now the 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.
spk16: Yeah, so, Tessie, thank you for the question. I think one of the first things is that to finish out the cohort three took longer. We ended up having a patient that qualified and something happened and we had to end up dragging out the last patient. And so that was part of one of the problems. One thing we saw in the cohort one day that we did put out is 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 going to behave like some of our enzymes, so we're learning a little about it. So our take was we need to go at least six months of data from the last patient in, and that's what the timing is. And you have to add on to that time to clean the data. It is an international phase 2-3 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 plan for heading into phase three.
spk03: Thanks, operator. Next question, please.
spk18: Thank you, Sal. The next question we have comes from Kristen Kluska of Council Fitzgerald. Please go ahead.
spk07: Hi, congrats on a great quarter. On citrusumab, 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 a reason to think that both reducing the fractures and putting down better bones has the potential to have an impact on pain.
spk16: Yes, our impression from the phase two patients, particularly with their increased activity, they're feeling better. They're having less pain. And while we talk about fractures all the time, OI patients have weak bones. And what that means is lots of micro-fractures. So if they do some heavily strong activity, they'll feel terrible the next day because they probably induced a bunch of micro-fractures. 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. And so 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, Sertuzumab a really important therapy for OI.
spk07: 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 risks? 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.
spk16: 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, and 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 actually stimulate their bones and to lay down the bone where their bone is weakest, it will actually enhance their bone strength further. So I think it will have a beneficial effect for them to be more active with sports or anything else. So we're not worried about the moral risk of getting more fractures. We think it's part of a healthy pattern toward more activity, stronger bone, and better lives for these OI patients.
spk18: Thanks, Emil. Thank you. The next question we have comes from Anupam Rama of JP Morgan. Please go ahead.
spk05: Hi, everyone. This is Priyanka on for Anupam. Just a quick question from us. For UX 111, 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?
spk16: 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 Andelin. They're derived from the nationwide children's people. They know their stuff. They do 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 agency about exactly what needs to be in a BLA. And 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, but we're expected to get there this year.
spk05: Thanks so much for taking our question.
spk03: Operator, next question, please.
spk18: Thank you. The next question we have comes from June Lee of Trace Securities. Please go ahead.
spk02: Hey, congrats on the strong quarter, and thanks for taking our questions. 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 GTX1 or 2 may be a better option for patients than Ionis 5.8.2? In other words, as patients consider enrolling for either GTX I wanted to, or Ionis' study, what would be the selling point for your program? Thank you.
spk16: 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-4 cognition achievement over longer periods of time, 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 angioma at this point.
spk02: Thank you.
spk18: Thank you. The next question we have comes from Morty Graycroft of Jefferies. Please go ahead.
spk00: 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 three, or what scenarios could require further optimization?
spk16: Thanks, Maury. I think 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 attrition. that indicates that they are now detoxified 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 ceruloplasm 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.
spk00: Got it. That's helpful. Thanks for taking my question.
spk18: Thank you. The next question we have comes from Joseph Schwartz of Learing Partners. Please go ahead.
spk19: 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 of success for approval. And along the same lines, can you remind us of our understanding of what a clinically meaningful benefit would be on the Bayley-4 endpoint? Thank you.
spk16: Well, first off, they agreed to a continuous variable analysis for the Bayley-4, 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 responder as part of the MDRI. which will support the clinical uniqueness. 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 two, which is achieving a majority of patients into the double-digit range of Bayley-4, 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-4 as the primary, The other endpoints are part of the story, and the value of it, as we see it through the eyes of the MDRI, is this combination of factors that is a change of life for patients. So I'd look at the big picture. The Bayley-4 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 phases 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 three, what we've already shown you in phase two, I think we're in good shape.
spk18: Thank you, Sal. The next question we have comes from Yaron Werver of TD Cohen. Please go ahead.
spk12: All right. Thanks for including us as well. Maybe I just have one and one follow-up. Emil, maybe just an angel in 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 three? And is there going to be a longer look as a secondary endpoint? And then just on GSD1A, 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 in the mid sort of one million or so. I don't want to speak for you, but how big of a market can we think here? Thank you.
spk16: 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 90 percentile. Even if you assume the placebo group had three times the natural history, three or four times the natural history rate, we still had well more than 90 percent power. In fact, with the typical natural history control group effect, we would be well above 95 percent power. So it is very well powered to see effect sizes we're seeing right now, which were into the double digit range. Uh, 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 what the powering on Angelman with regard to GFC one, a 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, their brittle nature of their disease. And 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 phase three, 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 cornstarch 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 the patient population, and we expect patients to want to get dosed. And we think that the key to gene therapy's 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 a bit too early. We have said in the past that pricing in the one to two million range is possible. I think price points have gotten even higher for some programs. But we haven't set down what our plan is. We're going to look carefully at this and come at it. But I think GST1A is a very reasonable and important opportunity. I think it will do well, and I think it will be an important new therapy. I expect it to perform more like some of the other programs where there's high levels of urgency.
spk18: Thank you, sir. The next question we have comes from Jeffrey Hunk of Morgan Stanley. Please go ahead.
spk15: Hi, this is Michael Riad. I'm for Jeff Hunk. Thank you for taking our question. Going back to citrusumab 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 profiles, which is not viewed 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.
spk16: Well, you know, I think each patient is going to 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 three or four years of age and ending up in a wheelchair. So that would be what you could do when you're treating kids who are 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, it's still highly valuable in an adult with Type 3 or 4. For Type 1, probably the sphere half of that population will have enough fractures where at any age, young or old, it's going to 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 get Type 1s treated There may be some type 1s who are milder, don't have as many fractures, and there might not be as much addressable need in those patients. So we would expect all type 1s. What I can say from the data we've shown you, though, the type 1s do really well on the treatment, as do the type 3s and 4s. So 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 and with any of these diseases.
spk15: Thank you. I appreciate that. I'm out of color. And then, um, for Angelman, um, I just want to circle back to something. So obviously we saw like competitor data that showed good responses up to six months and the phase three is up to 48 weeks, but that makes the phase one to giving them a bit of a more unique insight into those 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.
spk16: Are you asking about our data or someone else's data? I didn't quite understand.
spk15: I'm asking about like the phase one, two, like how the, that phase one, two data, um, especially like the larger term data can. Yes.
spk16: 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 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 demonstrate the shift from the control group, get the drug approved, but the long-term and continued improvement will be why patients stay on drugs and why the product will penetrate the population if successful in Phase III.
spk15: Thanks so much for answering our questions.
spk18: Thank you. The next question we have comes from Jack Allen of Baird. Please go ahead.
spk10: Great. Thanks so much for taking the question. Congratulations on the progress over the quarter. I wanted to ask on citrusumab, I guess a few little parts of 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 citrusumab. 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 citruzumab 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 comment 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.
spk16: 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 three and to be prepared as necessary to file a BLA if we're able to hit an interim. But 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 that have been on the 17 to 24 months have continued to do extremely well and are, it's very encouraging and transformative. So we definitely think that's true. We may put it out at some point in time, but I think most people are, eyes already turned toward interim analyses in 2025. So we haven't committed to other, more data yet. With regard to the ORPIT type of patients, We did enroll more Type 3s and 4s. We now put up the ratio, but in the first Phase 2 study, we had 17 Type 1s and 7 Type 3s and 4s, and it's a significantly larger Type 3s and 4s 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 number of those. I think actually the Phase 2 data stimulated them to get involved, because before they were apprehensive, once they saw data, then the doctors started putting in their most 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.
spk10: 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 3 portion of ORBIT? I guess, did you enroll potentially more severe patients than expected? Any thoughts on how that may impact the power?
spk16: Well, we originally started with a 195-patient study. And then when we saw our first look of data at six 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. You want to get enough type 1s, type 3s, and 4s to look at the subsets, right? And you also have P's and adults, right? So you have to look at the age subsets, right? So the number 150 you can look at is the overall power, and then I'd 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 3s, 4s, or 1s. So that was one of the drivers in maintaining the number of 150. I think with the fraction 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 in the age groups, what we put, I think, was a good design that will capture the amount of data across all types of OI.
spk10: Got it. Thanks so much for the color, and congrats on all the progress.
spk16: Thank you.
spk18: Thank you. The next question we have comes from Lisa Walter of RBC. Please go ahead.
spk08: Oh, great. Thanks for taking our question. This is Lisa on Perluca. 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 30th 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.
spk16: Yes. So the sunsetting of being able to get them, being 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 if we file for UX111. and DTX 401, 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 ultragenics. has 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 it hasn't happened yet. And election year is a crazy time to do things, but we think it's something that rare doesn't matter with regard to what party you are if you have a rare disease. So we hope the PRV will get the support. We're certainly providing it.
spk03: Thanks, operator. Can we go to the next question?
spk18: The next question we have comes from Lisa Baco of Evercore ISI. Please go ahead.
spk06: Hi, this is streaming for Lisa. Thanks so much for taking our questions. So we noticed that Mgen is running an open-label phase three study for romosaltzumab in OI, and they have indicated that if the phase three study is positive, they may have an opportunity to pursue approval and launch an OI. So we're just wondering, what implications do you think it would have for cetruzumab if Mgen decides to pursue approval in OI? Thank you.
spk16: All right, well, that's new to us. They've already given us the intellectual property access, so I don't think they've had that much interest in it. 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 ClinTrials.gov or the European version of it. Right now, they're getting substantially less bone marrow density. at the dose levels they're using. So we're a superior treatment in terms of our bone marrow dense 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 three is not optimize the drug nor the presentation for OI. And so I really don't have concerns right now because we know our data is far superior. For them to get to our data, they would have to change their dosing dramatically from phase three. which is not likely to happen at this point. So at this point, I think there 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 in 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 Angen by this before. I believe that the osteoporosis has been their main space. And it hasn't been listed as part of their rare disease franchise at all. So, I'd be surprised if they're changing that.
spk06: That's helpful. Thank you.
spk18: 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.
spk03: Thank you. This concludes today's call. If there are additional questions, please contact us by phone or at irultragenics.com. Thank you for joining us.
spk18: Thank you. Ladies and gentlemen, that then concludes today's conference. Thank you for joining us. You may now disconnect your lines.
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