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spk18: Good afternoon and welcome to the Ultragenyx third quarter 2023 financial results conference call. At this time, all participants are in a listen-only mode. At the end of the prepared remarks, you will have an opportunity to ask questions during the Q&A portion of the call. It is now my pleasure to turn the call over to Joshua Higa, Vice President of Investor Relations.
spk11: Thank you. We've issued a press release detailing our financial results, which you can find on our website at ultragenics.com. Joining me on this call are Emil Kakas, Chief Executive Officer and President, Eric Harris, Chief Commercial Officer, Howard Horn, Chief Financial Officer, Eric Krambes, Chief Medical Officer, Aaron Olson, Senior Vice President of Corporate Strategy and Finance, and Ted Huizenga, Chief Accounting Officer. I'd like to remind everyone that during today's call, we'll be making forward-looking statements. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. Please refer to the risk factors discussed in our latest SEC filings. I'll now turn the call over to Abel.
spk10: Thanks, Josh, and good afternoon, everyone. Before we get started, I'd like to welcome our new CFO, Howard Horn, to the call. To say he has hit the ground running is an understatement, He already has an Ultragenetics Analyst Day and a financing under his belt. We're happy to have him on board as we prepare for our Catalyst Rich 2024. It was great to see many of you at our Analyst Day a few weeks ago. We hope that the new data shared at the event, along with the positive clinical impressions of the investigators on two of our programs, showed you why we have confidence in our lead therapeutic candidates, in their potential to transform debilitating disease with limited or no treatment options. We kicked off the day by sharing new data from the ORBIT study for citruzumab in osteogenesis imperfecta. It has been prevented a few days earlier at ASBMR, the American Society for Bone Mineral Research, 2023 annual meeting. Interim data from the Phase II portion of the study demonstrated that citruzumab significantly reduced the analyzed fracture rate by 67%. after at least six months of treatment. It continued to demonstrate ongoing substantial increases in lumbar spine bone marrow density, reaching 19% in just six months in the younger patients. We also provided an update on our GTX102 program in age and syndrome. The data we covered was longer-term extension data from the dose escalation cohorts in the Phase 1-2 study. And it showed the treatment with GTX1-2 resulted in clinically meaningful improvements across multiple domains through both the loading and maintenance phase of treatment. The improvements we saw in Bayley and the age and severity assessments, formerly known as the CGI-S severity scale, were also supported by objective changes in EEG and comparisons to natural history. We also looked at the emerging first-ever development changes from three of the original U.S. patients. When these patients stopped receiving GTX1 and 2, they lost these first-ever developmental gains, but were able to gain these skills once they started treatment with new dose and regimen. Other patients also saw many first-ever development gains, which gives us confidence in the potential transformative effect for this neurodevelopmental disease. These first errors are very important to the families and give clinical meaningful to the changes we are seeing in the quantitative assessment. The third program we highlighted was our UX701 AAV gene therapy for Wilson disease. We provided data on the five patients in the first lowest dose cohort. At 5E12 GC per kilo, four of the five patients showed improvements in copper trafficking and had begun tapering off standard of care with key layers and or zinc therapy. This includes two of the earlier treated patients who are now completely off standard of care and doing well. Eric Kramiz will provide more detailed updates on these programs later in the call, but it's clear we have three large value programs all generating data that meaningfully de-risk the probabilities of their success. Now I'll turn the call over to Eric Harris to provide an update on our commercial efforts for the first quarter.
spk09: Thank you, Emil, and good afternoon, everyone. After five years of successfully commercializing Prospita in North America, this responsibility was transitioned to Keowah Kiran on April 27, 2023. As part of the transition, a small orthodontics field team and patient support services team was kept to help the Keowah Kiran field team find and start diagnosed patients while ensuring a smooth handoff. With the combined field efforts, The demand for StarForms throughout this year has remained strong and is greater than what we saw during the same period last year. In recent months, the majority of the StarForms have come from adult patients, which further supports our strategy of expanding the search into community physicians to find these patients. The two teams are working hard to ensure patient and physician continuity while continuing to identify new prescribers and patients. Shifting to Latin America, shifting to Prospita in Latin America, as of Q3 2023, there are over 460 patients on reimbursed therapy, which includes approximately 50 new patients who began commercial therapy in this quarter. This year alone, we have converted approximately 150 new patients to the commercial drug in this region. The Latin America team has continued to build solid momentum further strengthened by the recent reimbursement approval for pediatric patients from the largest public payer in Mexico called IMSS. CRISPR is approved in six countries in Latin America, including Argentina, Brazil, Chile, Colombia, Mexico, and Peru. Brazil continues to be the largest market in Latin America and we continue to see growing demand in this country. While the uneven ordering patterns in Brazil drive some quarter-to-quarter variability, the underlying demand remains strong. Today, we are reaffirming the prospeeder guidance we issued at the beginning of the year. The range of $325 to $340 million includes all regions and all forms of prospeeder revenue. More specifically, it includes prospeeder product revenue from Latin America and Turkey and the cash and non-cash royalties from North America and Europe, and the collaboration profit share revenue prior to the transition. For DiGioia in North America, the demand for STAR forms remains strong. In the US, we have added nearly 19 STAR forms and converted over 70 patients to reimburse throughout this year. We continue to expand the number of treaters of DiGioia in the US. adding 30 new prescribers this year, including some healthcare professionals in the Centers for Neuromuscular Medicine. In Canada, we continue to make progress following a positive opinion from CADET, completing PAN-CPA pricing negotiations and signing listing agreements. Outside of the U.S., there continues to be growing demand for the GOBI. In Latin America, Our commercial teams are continuing to identify more patients, and we expect demand will continue to steadily increase over time. Across Europe, we continue to deepen the awareness for LCF ALD key stakeholders and address the high unmet medical need through main patient and early access programs. Requests are coming from across all major European markets, as well as Greece, Israel, and the Middle East. Today, we are reaffirming our 2023 Global De Jovi Revenue Guidance range of $65 to $75 million, the range we announced at the beginning of the year. Lastly, on EFKISA, we continue to make progress in major markets in Europe and the Middle East. EFKISA is now approved in Germany, where we have started to convert patients to commercial drugs. In many other countries, the demand is steadily growing, as patients gain access to F-PESA through various early access programs. In Canada, we received marketing approval from Health Canada for adult and pediatric patients aged five years and older with HOFH. We also continue to make steady progress in Japan, where we have meetings scheduled later this year with the Ministry of Health, Labor, and Welfare to discuss pricing and reimbursement. Across all regions, we have received overwhelmingly positive feedback from KOLs and patients. They have continued to highlight the significant unmet need for this disease and the importance of this potent new treatment. We continue to respond to many urgent requests for early access, and our teams will continue their efforts to bring this product to people living with AQFH as quickly as possible. In closing, we are reaffirming our 2023 total revenue guidance range issued at the beginning of the year of $425 to $450 million. With that, I'll turn the call to Howard to share more details on the financial results for the quarter.
spk07: Thanks, Eric. It's great to join the team for today's call. Before we get into the numbers, I'd like to thank Ted, Erin, and their teams for all of their contributions over the last year. They implemented a number of important initiatives around financial discipline, which have contributed to the strength of our current financial position. I will briefly summarize the financial results that were included in the press release we issued earlier today. Starting with revenue, our total revenue for the third quarter was 98 million. CRISPEDA revenue for the third quarter was 75 million, which included 50 million from North America, 19 million in product sales, primarily from Latin America, and approximately $6 million in European royalty and other product revenue. As we have previously disclosed, the third quarter U.S. Crest Vita revenue was negatively impacted by a one-time decrease in channel inventory related to Keoghan's change from Ultragenyx-labeled product to Keoghan-labeled product as part of the transition of North America commercialization responsibilities. Again, this is a one-time change. and we expect Crispita channel inventories to increase to more normal levels at the end of the year. The Jolvi revenue for the third quarter was 17 million, with North American demand driving 25% growth versus third quarter 2022. Shifting to expenses, our total operating expenses for the third quarter were 243 million, which included R&D expenses of 157 million, SG&A expenses of 75 million, and cost of sales of 11 million. Operating expenses for the quarter included non-cash stock-based compensation of 35 million. For the third quarter, net loss was 160 million, or $2.23 per share. As of September 30, 2023, we had 524 million in cash, cash equivalents, and marketable securities. After the end of the quarter, we raised an additional 326 million, from an underwritten public offering of common stock and pre-funded warrants. Through the third quarter, net cash used in operations was $391 million. We expect fourth quarter net cash used in operations to be around $35 million, driven by anticipated strong fourth quarter revenues and factoring in expected changes in working capital. As a result, we now expect full-year net cash used in operations to be around $425 million. The team has worked hard over this past year to ensure we are in a strong financial position, and we will continue to build on these efforts going forward. Now I'll turn the call to our CMO, Eric Crumbes, who will provide an update on our key clinical programs.
spk13: Thank you, Howard, and good afternoon, everyone. Emil mentioned the key clinical updates we shared at Annals Day, and I'll provide just a bit more detail on our priority programs. starting with UX143 or citruzumab for the potential treatment of osteogenesis imperfecta. The data we presented at the analyst day supports our view that this is a disorder of inadequate bone production as much as it is about defects in collagen. Across the 24 patients enrolled in the phase two portion of the ORBIT study, we saw an improvement in bone mineral density Z-score of 0.85 at six months. Importantly, The subset of 5 to 12-year-olds saw nearly a 20% increase in bone mineral density, with a Z-score change of 1.19. These improvements in bone mineral density across the 24 patients treated in the orbit phase 2 translated to a 67% reduction in the annualized fracture rate following treatment with cetruzumab for at least six months. 20 of the 24 patients did not experience any new fractures in the six-month following treatment with citruzumab. For the four who did have a radiographically confirmed fracture, many of them occurred early on in treatment or had a traumatic precipitating event. The data is all the more compelling because many of the patients in this study were previously treated with bisphosphonates over the two years prior to dosing with citruzumab. During this time, these patients continue to see a high annualized fracture rate with many fractures occurring with very minimal activity. These types of fractures are referred to as fragility fractures, and examples include fractures occurring during sleep or when transferring out of a chair. What we heard from two principal investigators who joined us at Analyst Day is that they are not seeing fragility fractures in these studies patients treated with cetruzumab and that many of these kids are now feeling strong enough to engage in more physical activities with friends and family. Next, turning to GTX 102 for the potential treatment of Angelman syndrome, where we showed clinically meaningful improvements across multiple domains for the patients in the loading and maintenance phases of the dose escalation cohorts four through seven. With the long-term extension data, We showed improvements compared to natural history data and supportive EEG data, providing further evidence that the changes we are seeing are meaningful and improving over time. We also shared data from three of the original US patients who stopped and restarted treatment. These patients gained, lost, and regained a number of skills, including following complex directions, communicating needs and wants, and improved behavior in sleep. These changes show the importance of GTX102 to enable continued development in these patients with the hope that they will continue to learn and develop new skills. Dr. Elizabeth Berry-Kravis, who is a principal investigator for the study, took us through a few video examples of what these developmental improvements translate to for her patients and their caregivers. Dr. Barry Kravis has been working with Angelman patients in our clinic for decades and noted that it can take years for these patients to learn a single new skill. So the fact that these patients are learning multiple things in such a short amount of time is remarkable. Enrollment in the dose expansion cohorts, cohorts A through E, continues to go well and we anticipate sharing data from at least 20 patients who have been on therapy for at least six months in the first half of 2024. Lastly, UX701 for the potential treatment of Wilson disease, which is a disorder of copper trafficking. As Emil mentioned, we are seeing a response in four of the five patients treated in the first dosing cohort with patients two and three completely discontinuing their chelators and or zinc. At analyst day, we said that cohort two receiving a dose of 1A13 has been fully enrolled. The DSMB is scheduled to meet soon to review the available data, which will enable initiation of dosing in the third and final cohort in stage one. The five patients for this last dose escalation cohort have been identified and meet enrollment eligibility. We expect dosing in this cohort to complete around the end of the year. The improvement in copper biomarkers and ability to reduce current standard of care are promising signs of the establishment of normal trafficking of copper in these patients, and we look forward to sharing additional progress with this important gene therapy program. I'll now turn the call back to Emil to close with the key upcoming milestones and provide some closing remarks.
spk10: Thank you, Eric. I'll summarize the key upcoming clinical catalysts before we open up the Q&A. Starting with UX143 for osteosympathetic perfecta. Enrollment in both the Phase III studies is going well with strong support from the medical community following both of our data releases this year. We're enrolling at 50 sites around the world and are targeting complete enrollment in the first quarter next year. We also expect to provide another longer-term data update from the Phase II portion of the study next year. Next, GTX102 and Angelin Syndrome. Based on the patients who are currently enrolled and dosed, we are on track to provide an update on the expansion course in the middle of the first half of 2024. As we have said, this will include at least 20 patient data. We've been on therapy for at least six months and include long-term efficacy data on early enrollees and a safety update on the total exposed population. Closing with our gene therapy program, GTX401 for GSD1A dosed the last patient in pivotal study earlier this year. We're now in the 48-week window and expect to unblind and share this phase 3 data in the first half of 2024. US-111 for Sanfilippo syndrome. We are continuing to see nasal clinical responses in these patients, and we're working the FDA around biomarker data to help support an accelerated approval filing. DTX-301 for OTC is enrolling patients in the phase 3, and we expect the last patient to be dosed in the first half of 2024. UX 701 for Willis disease should have all patients dosed in Stage 1 this year, and we expect to provide safety and efficacy data on all of these patients in the first half of 2024. We've worked hard over this past year to ensure we are in a strong financial position heading into 2024 and beyond. We continue to see growing demand for our commercial products and completed a financing that gives us the ability to advance our large value program through meaningful inflection points. We've been employing more aggressive financial discipline, including realigning our headcount, restructuring in places, and doing the work we need to make sure we're putting the people and capital where we have the ability to generate the most value. Alternatives have come a long way since our humble beginnings. As I said at Analyst Day, we expect to have around 8 to 12 approvals in our first 15 years post-IPO, and these are in extremely debilitating disease with urgent need for treatment options. I think that really demonstrates the responsibility we feel to lead the future of rare disease medicine. With that, let's move on to your questions. Operator, please provide the Q&A instructions.
spk18: Thank you. As a reminder, to ask a question, please press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1-1 again. One moment for questions. Our first question comes from Manupam Rama with JP Morgan. You may proceed.
spk06: Hey, guys. Thanks so much for taking the question, and welcome, Howard. Hope you're well, man. So, I got a quick, broader question here, which is, what are you monitoring here for the Sarepta DMD gene therapy regulatory review process that could maybe potentially read through to your broader gene therapy efforts and pipeline? And then on one of your gene therapy programs, specifically 401 and You know, we heard a little bit about that program at R&D Day, but maybe you could help us define a win scenario for that program when you flip the card and maybe help us understand the market opportunity a little. Thank you guys so much.
spk10: Very good. Thank you for the question. So, as everyone knows, the disruptive phase three in blinding showed the primary endpoint of the NSAA, but hit strong to other endpoints. I think it shows that the drug is working. I think the NSA is a terrible endpoint, and frankly, I've said to people we would never want to work with that endpoint because it's just a clinician score, so it's not so surprising. I think the drug shows it's working, and it'll be up to SRAP to manage that forward. I think what I would say in the broader context for our own program is that the ability to deliver microstrophically is having an important clinical benefit in these patients. It's still a first step in a path toward improved care for these patients, but we think, I think in general, it says that these microstrophic gene therapy programs can work, and we're still encouraged and still pressing our own program ahead in development. With regard to 401GSE1A, the program, you know, we think there's something around 68,000 patients, you know, and about a fourth of that would be U.S. patients. The The majority of these patients, like 80 plus percent of the patients are null, have null or are very essentially no enzyme. What that means is 80% of the patients are severe. That means 80% of the patients are at risk of dying if they miss a dose of cornstarch. These are the patients that have essentially a gun to their head taking cornstarch every day. The driver for adoption is the peace of mind of knowing I'm not going to die if I forget to take my cornstarch. And we think that's a big driver. We believe... It's one of the reasons why the phase three trial enrolled so quickly. People really wanted to get out of this treadmill that they're on with cornstarch and sugar control and the fear of every night being a potential, you know, risking death if something went wrong. Or if they go and exercise, they could collapse and be hypoglycemic. So we think there's a big demand and drive. Of course, cornstarch is not commercially costly, but I do think the peace of mind and stability of people who can live a life instead of one full of fear. I think it's big. And we have high hopes that the adoption of the treatment will be more aggressive and brisk, just as it was in the enrollment of the trial, which enrolled everywhere. In fact, we had a lot of people upset when we closed enrollment that couldn't get in the trial. So we think the demand is going to be there. And while it's not a huge program, we think 8,000 patients is a substantial one, and we think that there will be early adoption for that program. And I do think that the clinical demand and need is important. I think we've seen it for that program, so I'm pretty encouraged so far.
spk08: Thanks so much.
spk18: Thank you. One moment for questions. Our next question comes from Dagon Ha with Stiefel. You may proceed.
spk01: Great. Good afternoon. Thanks for taking our questions. Two, maybe on GTX102 and the citruzumab. Just wanted to clarify on Satruzumab, Emil, did you say enrollment completion in 1Q24? Is that for both orbit as well as cosmic? And are you placing any protocol restrictions on strenuous activity? I mean, it's encouraging there being more active and fearless, but in terms of endpoints, I wonder if that could kind of create a confounder. For GTX 102 update in first half 24, what kind of data should we be expecting? You had ASA, MDRI. as well as Bayley 4, but if you could frame that for us, that would be great. Thanks so much.
spk10: Very good, Daniel. Thank you. So for the Chizumab, we're talking about both Orbit and COSMIC in terms of finishing enrollment. I think we're likely, but the main one we're talking about is Orbit, which is the main driver. I believe both of them should get done in that time frame. And in terms of this controlled exercise or the hazard risk of someone feeling better and exercising, Well, that's already what's happening in phase two. People were a lot more active. And what was actually on the plus side is that they were active and a lot of them were wherever falls they had, they didn't have fractures necessarily. So while there is some risk that they might be doing more, there was one person who played volleyball and they hadn't been playing. We're actually overall feeling that the pattern of having falls and fractures seems to be better. And so our net effect overall is we think even with increased activity, there will be a reduction in fractures. which is really the best thing possible, that if the kids are going to be active and to have a reduction of fractures while being active. So we're not so worried about the, let's say, the noise of having more fracture risk at this point. It looks like you still see the effect well, even if there is some risk there. Now, with regard to GTX1 and 2, I expect the data to be many of the same things you've seen, which is the Bailey's, which we'll compare, of course, the natural history data, for the main three endpoints we talked about. There were other three that we looked at for the ESA. There are other endpoints. We didn't describe all the endpoints we had. We had said at the meeting that things like the Vineland and others had a very similar pattern of response to those. But I would look for data to be very similar to the package of data that you saw. We'd probably be doing something very similar to what you saw before in terms of comparison and natural history and the ESA. We'll try to include enough information to interpret the quantitative changes and the meaningfulness of those changes, which I think is one of the debates. And we're certainly going to look at emerging skills as well in those patients as best we can. So those are the things I think you'd expect to see. It should be 20 patients, six-month data. There will be probably 10 patients that have longer data out the 254 and more than 30 patients worth of data of any type. So Should be a pretty robust set of data, so I'm looking forward to that.
spk08: Thanks. Next question. Thank you.
spk18: One moment for our next question. Our next question comes from Jeffrey Hung with Morgan Stanley. You may proceed.
spk05: Hi. This is Michael Riad on for Jeff Hung. Thank you for taking our question. For citrusimab, how do you think regulators will view the clinical benefit for younger patients who are still developing versus adults who are more or less finished growing? Is there any appreciation for the ability to prevent fractures and complications preventively like bone deformations? Thanks so much.
spk10: Well, I think you're hitting on a really important thing. Let's talk about what the FDA asked for. They wanted to have the major clinical fractures excluding fingers, toes, and skull as the endpoint because they feel those are most clinically meaningful. However, whatever they think is one thing, they're dealing with fractures from osteoporosis. The truth is what you talked about is really important, that is the vertebral fractures and other types of fractures that result in deformation of the bone are actually things that drive very poor outcomes. Our trial, which will have pediatrics and also have some very young group patients, will look at not just clinical fractures, but also vertebral fractures and other fractures, which we think will benefit. So I think we'll be able to show the clinical fractures and hit the FDA's required endpoint, but we hope to be able to expand that to talk about other aspects of the disease, particularly in the very young patients in the COSMIC study, and to be able to show how support for their vertebral palms you know, would not result in the kind of degeneration, degradation that leaves them all to be wheelchair-bound as, you know, five or six-year-olds. I think that would be an amazing result. We're going to see what we do. But based on the very substantial lumbar spine bone marrow density improvement of 20% in some of the young kids, we kind of expect their spines to be strong and to change the future of not deforming like they've had in the past. So I would say we can prove the FDA and get our approval. but the broader acceptance of the treatment and its reimbursement will be supported by the rest of the body of data, which we are including in our plan.
spk05: That's really, really helpful. Thank you so much for your response.
spk18: Thank you. One moment for questions. Our next question comes from Yagal Nokomovitz with Citi. You may proceed.
spk02: Hi, team. This is Carly on for Yagal. Thanks for taking our questions. We had one commercial question. It looks like you're expecting a pretty significant reacceleration in revenues in the fourth quarter in order to meet the guidance range. I know you mentioned an inventory impact to Crespita during the third quarter, but can you talk a little bit more about your assumptions driving that acceleration in revenue that you're expecting? Thank you.
spk10: Sure. Let me, I'll hand it over to Eric. The fourth quarter has a lot of differences in how things perform. There's always a lot of lumpiness as well, but Eric, if you want to deal with what you think, how revenue is going to go in the fourth quarter?
spk09: Yeah, I think if you look at previous years, we've always had a strong fourth quarter, so it's typical seasonality, which will also this year will entail some inventory rebuilding following the NDC swap out. And as I stated in earlier, demand remains very strong. In fact, our demand in stock forms is higher than it was at this point last year. So we remain confident that we'll see a strong fourth quarter.
spk10: Yeah, I think if you go back and look, you'll see every fourth quarter has been an up quarter. So we're on track. We think pretty good about where we are in the business.
spk02: Okay, great. That's helpful. And then maybe just one follow-up related to the Wilson program. Can you give us how you're thinking about the size of the addressable population for a gene therapy approach in Wilsons and maybe what you're hearing from KOLs about the proportion of patients not well managed on chelators and on the more severe end of the disease spectrum that could be addressable? Thank you.
spk10: Yeah, I think the The Wilson market potential is an important question. The 50,000, 60,000 patients, probably more because it's underdiagnosed in my view. And you can look at it as maybe the 20% of patients that aren't well managed is the core indication. But I think with the dropout of the Alexion AZ chelator as a competitor and showing that just chelation is not good enough to make patients better, the door is open. to the idea that improving copper distribution could make patients feel better, do better than you can get just with a chelator, which means it might not be just the 20-plus percent that have problems with their chelators. It could mean more of the majority of the patients with Wilson. We're encouraged that the patients are getting off their, yeah, the chelators, but I think I think we're also really encouraged that the copper distribution seems to be improving, even at the lowest doses, and that patients seem to be feeling really good. My hope is if you restore copper distribution, that the effect of copper deficiency, which is occurring in Wilson disease, overlaid on top of copper toxicity, is a real factor. And if we can make people feel a lot better and perform better, I actually think there's a potential for this to be an indication that becomes a majority of patients. Because our ability to manufacture with the Pinnacle platform in our own plant keeps the cost really low, it also means we can manage the pricing in a more intelligent way that would enable a larger fraction of these patients to get put on therapy and actually build a bigger business model out of it than one based on a $3 million impression kind of price point, which I think makes it more challenging. So we look at the opportunity here as potentially larger than the initial views if if we can make patients feel better, do better, and I think there's a real chance for that with the Wilson gene therapy.
spk08: Great. Very helpful. Thank you. Thank you.
spk18: One moment for our next question. Our next question comes from Tazin Ahmad with Bank of America. You may proceed.
spk04: Hi. Thank you so much for taking my question. Emil, I maybe just wanted to clarify one point. I'm sorry if it was already asked before, but when you talked to the FDA about downsizing the OY Phase III trial, you were supposed to get specific feedback on that. Just wanted to hear your thoughts on what FDA's view on that particular request was, or if you're still waiting to hear back. Thanks.
spk10: Yes. We haven't really discussed the details of going through that, but The plan on the phase three with the addition of the interim assessments we think won't be a problem, but we haven't really disclosed any of the ongoing discussion with them, but we're comfortable with the ability to get the interim set. And besides the study, it's really up to us. In terms of safety, the exact trial size is well above 100 patients is more than adequate in size. We'll come up with a plan with them, but I'm not concerned about our ability to get that accepted.
spk04: Okay. Thank you.
spk18: Thank you. One moment for questions. Our next question comes from Kristin Klusko with Kent Everett Sherald. You may proceed.
spk04: Hi, everyone. Thanks for taking the question. Can you provide any more color or thoughts around the timing of the interim analyses of the OI study?
spk10: Yes, the way the interims will be done, we won't be disclosing when they're happening. We've said there we'd expect a first one to happen this coming year. We want to make sure that patients had at least a certain amount of time of treatment before an interim would be done. And the original plan for the program was to operate off of the fracture information, how many fractures there were, essentially event-driven timing. So the precise timing we haven't disclosed. It depends a little on fracture numbers, et cetera. But we said that one error will occur next year, but we won't disclose exactly when. It'll happen in a controlled way, unblinded assessment by the DMC, so we won't know when it happens. So at this point, we'll all be waiting. But we're encouraged by what we're seeing and the potential the study could end early. But However, we feel when we have a drug that works and we're going to get through a positive phase three, at least we're feeling very confident about the ability of the product to get us there.
spk08: Thank you.
spk18: Thank you. One moment for questions. Our next question comes from June Lee with Truist Securities. You may proceed.
spk20: Hi, everyone. This is Mehdi for June. So on GTX 102, for the three patients whom regained some lost clinical benefits after redosing. So how do you best plan to highlight this significant observation for regulatory agencies? And is it at all possible that time to redose could explain some of these clinical benefits? And I have a follow-up question.
spk08: First of all, let's talk about what happened to those patients.
spk10: Those patients got anywhere from one to four doses, five doses, and had their clinical benefit effects of those newer emerging findings. They had the safety event. And then they're off treatment for, you know, on the order of like two years in which they lost all this activity. So two years off, they're pretty much washed out completely. No drug, no benefits. So when they start up again, they're really starting back from the beginning and regaining the same functions. In terms of the patient, there's one patient who's really gained a lot of words who had gained 9 to 12 words in the first period and now having been on consistent therapy for a longer period is actually up to 17 words. That's the patient also that's now swimming as well on their own without float support. So We think that the washout period takes them back to the beginning. It's not really, there's no relationship between what happened there and redosing effect. If you looked at what happened with naive dosing patients, we showed a graph at Animal State that showed a large number of patients having similar first ever emerging skills the first time they went on treatment. So we think there's nothing actually special going on with those three that's any different from any of the naive treated patients.
spk20: And thank you. The follow-up is on OI. So are there any specific reasons for preferential suitability of citrusumab on AI versus other anti-escalicidin antibodies like Avenity, SHR-1222, or the others?
spk10: Well, the only other one is Avenity or Romo, I guess we call it for short. Both target the same sclerosin. There are differences, though. Remember, our program, fituzumab, is a fully human antibody, which we think is a better choice for a long-term therapeutic because the risk of anti-drug antibodies will be much lower in a fully human antibody. We haven't seen them, so we feel ours is a better choice for a chronic therapy. We will have chronic dosing in our label. That is our intent. The ROMO is only 12 months. We think OI patients need continuous. And we've shown when you pull them off drug, as was done in the asterisk, they lose ground, even with this fascinate on board, whereas ROMO is basically given for a year and then supposedly the effects are locked in. But with OI, that's not true. You need chronic dosing. So the chronic dosing story will be ours. And finally, when we commercialize, we're going to provide the first-rate patient support we do to our rare disease patients, which is not something that's going to happen for an osteoporosis drug. The last thing I'll mention is that the presentation of that drug is a 210 milligrams in a pre-filled syringe. It's not very adaptable for different size patients and different amounts of drug dosing, whereas our presentation will allow weight-based dosing for each patient and optimization, which I think will be important in the ultimate care of these patients. Anti-sclerosis both can work, but I think ours will be a better choice for long-term use.
spk20: Thank you very much. Thanks for taking our questions.
spk18: Thank you. One moment for questions. Our next question comes from Maury Rakoff with Jefferies. You may proceed.
spk17: Hi. Thanks for taking my question. For 701 in Wilson, What goes into the decision tree for decreasing standard of care, and what is the target reduction in stage one? And can you provide more perspective around patient baseline characteristics for the first two cohorts, including baseline seroluoxidase activity?
spk10: Yeah, let me try a little top line, and then Eric, if you want to provide a little bit more detail. After they get the drug, there's a period of time where we watch and see how they're doing, and then we start titrating down their standard of care. And the goal in the trial is to get them off standard of care completely, like the first few patients. The others, I think, are going to get there. I'll let Eric talk a little about what the criteria are. At baseline, we haven't put out all the information in great detail, but maybe, Eric, you can provide a little bit, a high level on a few things to help with Lori's question. So standard of care, titration strategy, and then the baseline criteria.
spk13: Yeah, great. It's nice that we're able to do this in an open-label fashion because it gives us the ability to work closely with these investigators. But the goal really is to give all patients a trial of titration off of current standard of care. And what's nice about this disorder is you can monitor copper in a lot of very different ways, and certainly with a very big focus on urinary copper. But we feel with all of the types of ways we can measure copper, we really do have a good way to understand the effect of the gene therapy. Certainly, if any patients start seeing any signs and symptoms or biomarkers start trending in the wrong way, we will rescue them back to their original dose of chelators and things, but we really haven't seen the need to do that across the board or in a meaningful way. The ceruloplasm-based activity assay is interesting, and again, important because chelators and zinc have no effect on that. So the only way for ceruloplasm to exist is to have copper bound to it. And then with this assay specifically measuring the loading of copper onto ceruloplasm, these patients are coming in really with an activity below the lower limit of detection. So again, measuring the rise from there. So Still early days. Patients are definitely still increasing and benefiting from the transgene, but things seem to be really trending in the right direction for the great majority of these patients who have been dosed so far.
spk17: Got it. That's helpful. Thanks for taking my questions.
spk18: Thank you. One moment for questions. Our next question comes from Salvin Richter with Goldman Sachs. You may proceed.
spk03: Hi, this is Lydia on for Selveen. Thanks so much for taking our question. So just two on cetruzumab. So first, could you just provide a bit more detail on what exactly would trigger an early phase three readout? And then also, do you have any idea on pricing and reimbursement given the availability of ifosinates and romo?
spk08: Sure.
spk10: So the way the original trial was done, it was an event driven. That is the unwinding of the original final primary analysis is driven by having 100% of the fractures required to achieve the information needed. So it would be event-driven. And the original idea, certainly the interim, is to look at 60% and 80% of that maximum. Assuming a large treatment effect, we think we could hit persuasive statistical significance at maybe just 60% of the fractures required if the separation of the two is as high as 67%, as noted. So it really depends on the number of fractures. and the number of patients and the time of exposure. So it's a complex of those three points. So originally, the 100% expected to be somewhere between 12 and 24 months of exposure of the last patient in, and this would be less than that. But we expect that we would want to see at least nine months of data of treatment for the last patient in as our expectation. So it'll be fracture-dependent. but we would expect to see at least nine months of data from the last patient in. Nine months of exposure to the last patient in, as a minimum.
spk03: Thanks so much.
spk10: Yeah, the pricing reimbursement question. Well, obviously, Romo is out there labeled for osteoporosis, has a certain price point. It's actually at a lower dose with the way it's used, and What we're doing is actually in a much higher dose and will be optimized for OI. So you have to think about the dose differential for the two indications as one feature. The other, of course, is that our treatment will be chronic. And so the question people will have with the shorter-term treatment regimen is whether they should take Gromo longer when it hasn't been given longer, right? I think that becomes more of a barrier question about safety. and we'll have, in fact, the chronic data to show our drug can be given that way. We're going to think hard about our pricing strategies. You know, we're a company that looks at, you know, more moderated, responsible pricing as we did for Crescita. We think that would make the differential between it and Romo substantially less, and given the dose differential, would make it, I think, a not significant issue for the program. And given our support systems, our delivery, home infusion, home delivery of drug as we've done for Chris Vita for like 85% of the patients. There are going to be a lot of features that will help make this a lot more approachable for our rare disease patients that I don't think they'll get support from. So those are all factors, I think, in how it will play out. But we're really knowledgeable about the space because Eric and his team has been commercializing and 90% of those docs we commercialize Chris Vita to are also treating OI, right? There's a 90% overlap. So we really know how they are. We have a strong relationship. And that will put us in good position, I think, to compete. And in our view, we'll have the label. We'll have the best antibody. We'll have the right dosing, right regimen, the right team to commercialize.
spk08: Thanks so much. Thank you.
spk18: One moment for questions. Our next question comes from Yaron Werber with TD Cal, and you may proceed.
spk15: Great. Thanks, guys, for taking the questions.
spk12: First, just I think a quick one from us. Really kind of looking ahead to your kind of first half of next year, obviously you're going to have a pretty busy six months it looks like. So any sense that you can maybe give us on kind of the cadence of when to expect what, even if it's just kind of relative one before the other would be super helpful. And then one quick one on GSD1. Sorry if I missed this, but has FDA kind of given you any indication or do you already have a sense of how long after the top line readout you really need to continue to follow these patients? Really just trying to understand when you might be able or in a position to file and potentially launch with 401 if the data looks good. So thanks very much.
spk10: Good. So the case of findings, we actually have a table that has some of it. I have to say we've generally not provided extremely precise target of catalysts for various reasons. It is a busy first half. So buck your seatbelt. It's going to be fun. We're going to have a lot of good work coming out for you. But I don't think I can give you a blow-by-blow of exactly when all that's going to happen. But we'll have a table that will give you at least some ideas and ideas It will be a fun quarter. I'm looking forward because we have so many working programs and we're in such a good position. It'll be great to see how they're doing and be able to talk to you about them. Now, the question on GFC1 is how long to file. The agreement with FDA is that we could file with 48 weeks of primary data and including then long-term extension data from phase 1-2 patients, which are now out like five years, so there's quite a bit of data there. So, We think we have enough long-term durability data in hand, but keep in mind that the trial enrolled over a period of a good part of a year, so even if we have 48 weeks from the last patient, there'll probably be up to a couple years of data of the very earliest patients by the time we file, right? So I think I would expect us to be able to file within a reasonable timeframe. There may be other factors that we'll have to discuss with regard to the rest of the package and filing, but We'll be working to try to file as promptly as we can once we get all the pieces together.
spk15: All right, great. Thanks very much.
spk18: Thank you. One moment for questions. Our next question comes from Joel Beattie with Baird. You may proceed.
spk16: Thanks for the update. For the Amlogenics spinout, what's the latest plan and timing, and how much ownership does Autogenics plan to maintain?
spk10: Well, we do have a term sheet signed and a group of investors put together that we're filling out that syndicate. I can't tell you more yet about the details, but our expectation is for Ultragenics to own the majority interest in the spin-out, a majority interest in the spin-out based on what we'd expect. But it's not been finalized, and I wouldn't want to provide any more details until we get closer. But it's moving along. We have a lot of interest. Animal Day also brought out some new interest. I think there's a lot of belief that the MABS monoclonals against amyloid do work, but there's also a lot of room for improvement for something better, and we think this is one good option for how you might do a better treatment. So we'll put out more information when we get there, but we don't have a majority interest, and we'll hopefully just fill out that team and get that financed halfway through the end of the year is our goal.
spk08: Great. Thank you.
spk18: Thank you. One moment for questions. Our next question comes from Gina Wang with Barclays. You may proceed.
spk21: Thank you for taking my questions. Two very quick ones. The first one is regarding the Enderman program, the update next year. You said you will also have a 10 patient with a longer follow-up. Will you be able to share the Bayley other domains, if I look through, it's a social-emotional and also adaptive behavior. And regarding the multi-domain responder index, do you think that that could be a possible index that you could discuss with the FDA about possible approvable endpoint in the future? And quickly, regarding Chris Vitti, So regarding in LATAM, now the territory will be much more important for the revenue contribution. Any strategy you can think of can improve the penetration there.
spk10: Okay. Well, good questions. When I get to it, I'll let Eric do the CRISPR penetration strategy question. All right, I'll start first with the agement data. You asked about Bailey, other domains of the Bailey. A lot of domains, I think the adaptive and social-emotional are not very well designed for agement patients. They're designed for normal people, so I think they're not very good. Well, we will have data on adaptive behavior. We'll have Vineland, which has adaptive behavior, but we'll also have another scale called ABC scale that will probably be I didn't mention, but it's an aberrant behavior scale, which I think is maybe even more relevant to these patients for both clinically important. We talked about social, emotional, or adaptive type things. So we'll have some things, but I don't think the Bailey's not the best test for some of those things. We're focusing on the ones where I think it's sensitive. With regard to the MD, so that's 10 patients that we might have longer term data that is up to 254 or longer, and 20 that would have day 170. So we're trying to give you a better sense. We'll give you what we have on all of them. Now, for MDRI, we believe MDRI is a good strategy. We don't have FDA's agreement on that. They've seen it. I presented to them, including multiple senior leaders in the multiple conferences. We published a good paper on it. It's a very powerful method. I think it's a very appropriate method. The key thing with the MDI is that you really measure endpoints you can agree on anyways, endpoints that are meaningful, right? The only thing the MDI is is an analytical tool. How do you take five different endpoints and add up the results? And this says, look, I'm going to add up how many people responded in each of the endpoints to a clinically meaningful degree and add up those responses. So it's not conceptually that hard. you do get all the underlying data. So it's not like FDA is giving up anything by using that endpoint, right? They're actually getting all the underlying endpoints. So if they can get comfort around the Bayley scale for certain things and the ASA score or the Barrett Behavior Score or Violent or others as representative of those functions, then I think we can get them comfortable with MBRI as an analysis tool and how to get to the results. So lastly, let's talk about Chris Vita. Look, I think Chris Vita should be Majority of P's, in fact, I personally think every single kid who has XLA should be on Cofida and not all phosphate if they need treatment. And we still have room to go there. And we're working with our partners on it. I thought maybe, Eric, maybe you could say anything we might be doing to try to help them maximize the penetration of Cofida.
spk09: Well, yeah, just to reiterate, Blackhead is doing great. It's been very successful thus far. We'll continue with our current commercial efforts. Because really what's going to continue the strong demand there is the, what's really going to drive the growth there is as we continue to get formal reimbursement across the other countries, right? We've seen the significant uptake just recently in Brazil following the formal reimbursement, public reimbursement, as we work our way through reimbursement through the other countries. we'll see continued growth in the Latin American region.
spk10: Certainly in countries that have started treating patients, they would like what they see and they start adding patients. So there's a drive for use of the drug and formal reimbursement is definitely one of the pieces that will help get us there. It certainly has picked up a lot since Brazil got approved. We're encouraged. I think there's still more room to grow in Crescida. It's still in the middle of launch.
spk08: It's not plateauing out. It's continuing to grow. Thank you.
spk18: Thank you. One moment for questions. Our next question comes from Laura Chico with Wedbush. You may proceed.
spk14: Good evening. Thanks very much for taking the question. I guess I wanted to circle back on the potential amylogenics spin-out. You showed some intriguing data at the R&D day with respect to plaque reduction in the 5xFID models. Could you just remind us any data demonstrating effects on either anti-inflammatory or pro-inflammatory markers there following treatment with the product. And just out of curiosity, will there be any further data updates expected prior to the spin-out? It sounds like things are moving along pretty quickly. Thanks very much.
spk10: Yeah, so we focus mostly on the pharmacology of plaque rather than secondary markers, inflammation, et cetera. So I don't have more to offer you at this point. The one challenge I would say is when you're doing the way you do it in the mouth, injecting directly in the brain, there's an effect of putting a needle in the brain and how that affects things. To get to those models, I think you need to be doing real intrathecal treatment. And maybe in the rat model where you can do that, you can kind of look at those markers. But if you have to inject through the brain, I think it makes it a little more complicated to look at those aspects of the neurologic disease. We won't likely put out more data until the spit-out occurs. We are continuing to do some work. It's not a big burn factor, but there are some experiments going on to look at both the 2x FAD mouse and some other aspects of optimization. But we're really encouraged by the potential that we think is greater than the monoclonal analyzer reducing amyloid in the worst model out there, which is the 5x FAD. And so we think there's enough interest and With our systems and Pinnacle PCL manufacturing, it really puts us in position actually being able to approach a large market indication which, and I think it would be from a response we've seen from KOLs in our market work, there's a great deal of interest in something that wouldn't cause area inflammation but allow a single shot therapy for a treatment for a disease of this kind. We're excited about the spin out and we'll put more information out when we get it done as we progress.
spk14: Thanks very much.
spk08: Thank you.
spk18: One moment for questions. Our next question comes from Ed Arce with HC Wainwright. You may proceed.
spk19: Hi, everyone. This is Thomas Yip asking a couple of questions for Ed. I appreciate taking our questions. First, perhaps for 111 for central liposyndrome, can you discuss some major topics that you plan to discuss with the FDA in the upcoming meeting?
spk08: And what do you plan to achieve coming out of the meeting? Yeah, well, in the
spk10: NPS3A program, our main focus of these discussions is on how to qualify epinephrine sulfate as a biomarker for accelerated approval. I point out to you we're also measuring clinical data and we're encouraged by the clinical data as well. I mean, the patients have continued to gain ground, gain development skills over time, and I think that this shows that the gene therapy is working. While we could potentially get approval by just following these patients clinically, Our hope is to be able to get the biomarker accepted. There's been a challenge with the agency. I think Peter Marks has publicly supported the use of the biomarker, including this biomarker at the recent MPS conference. But we have to get them through the details of how that's done. I think as a company, we're as well versed as anyone in how to explain the biomarker and how to analyze the results. But it is a situation where you have a neurodegenerative disorder with a relatively slower progression through multiple years. And therefore, the qualification takes a little more work to figure out and support. But I'd say everything I've seen in our program and multiple other clinical programs from other parties shows that these markers represent the underlying disease and their reduction through either enzyme or gene therapy is showing a meaningful reduction that will have important clinical benefits. So we're confident about the value of the treatment and we'll continue to work with them on what it takes to qualify and move ahead. I will say for the program, we're also working on the CMC side of production. We had to take that over. That is going to take some time. So in any case, we wouldn't be ready to file until we were able to run the CMC side of the equation. This is not a priority program for the company, so we have managed it in a more capital-efficient way as best we can, but our hope would get the CMC straight as well, which will be part of the factor that will determine our ability to file it in addition to our discussion with the FDA.
spk19: Perhaps just one more question from us, this one for GTS-1024 and human syndromes. As we expect the expansion core data in first half of 24, what do we expect the median treatment duration among these patients would be and what are your some initial thoughts on possible registration or endpoints?
spk10: Well, the duration, most of the patients 20 will show will have only day 170. We've shown you that in the most recent extension data, the day 254 looks better than day 170. However, the dose loading, the average dose loading of the expansion course is higher than what we just showed you before. So they're actually getting more drugs. So our expectations by day 170 will see more effect is our expectation. We will have 10 patients that should take us through 254. Allow us at least a sense for how that's going. and give us an idea. So our expectation for a pivotal study would be that it would be a somewhere in the range of seven to nine month kind of study where we've loaded and gone through a few maintenance doses. We think that's the sweet spot for improvement and change without giving kids too many placebo intrathecal injections. You know, these are people's kids and you're putting, doing lumbar punctures in them. So I think that combination will give us enough time to separate, and we think it would be long enough. I'm sure the FDA would always want a longer study, but I think we're getting close to the one-year point, but I would hope that maybe it's going to be in eight to nine months would be a reasonable place to show substantial separation and look at day 254 as kind of a place where you could see a lot of movement in the development of these kids.
spk08: Got it. Thank you again for taking our questions.
spk18: Good. Thank you. I'd now like to turn the call back over to Joshua Higa for any closing remarks.
spk11: Thank you. This concludes today's call. If there are any additional questions, please contact us by phone or at irs.ultragenics.com. Thank you for joining us.
spk18: Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.
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