All righty, let's get started. Welcome everyone to the Tuesday morning of the 41st annual J.P. Morgan Health Care Conference. My name's Anupam Rama. I'm one of the senior biotech analysts here at J.P. Morgan. I'm joined by Malcolm Kuno and Priyanka Grover from the team. Our next presenting company is Ultragenyx, and presenting on behalf of the company, we have the CEO, Emil Kakkis. Emil. Thank you, Anupam. Happy to be here again today in person, hustle and bustle of J.P. Morgan again. It's great. We're happy to be back in the mode, and wanna give you an update on Ultragenyx, where we are today. This is our forward-looking statement. Our mission since 2010, the founding, has been going beyond every day to change the lives of rare disease patients. We've been successful in doing that with four approved products and five indications in that timeframe, treating more than 3,000 patients globally. We've done it with a precision and efficiency, 70% success rate for our programs. While we have four approvals and four products, we also have seven programs in clinical, five advanced stage programs. We've managed to fill the pipeline and advance those programs into pivotal stage as well. I think we've been extremely successful in moving forward the goal of going beyond and treating patients with rare disease. Our specialized approach is not maybe so unusual, but it's about making good decisions and being smart about how you go about understanding what's going on in a disease, understanding at a deep level, and really understanding the biology and picking the choices where you can change the future of a patient by fixing that biology. Then picking the right drug, and we're agnostic as to modalities, as we do different types of modes. We pick the mode that's really the best choice for that particular disease and biology. The thing that's also very important is how you get informed by the patient experience. Everyone wants to be patient-centric, but the question is what does that mean? Is that having a chief patient officer? Is it really getting connected and learning from patients of what's going on in their lives to understand how to design a trial? In our Crysvita program, for example, we found out talking directly to patients that stiffness was a critical component of their lives. It was their number 1 complaint, but stiffness has nothing to do with their bones. It has to do with their muscles. We built that into the program and proved that the drug actually helps. That was really important 'cause many people said adults would never get treated. Now more than 50% of the prescriptions are for adults who want the benefit of what Crysvita can provide. Same thing with Trureason, with Duchenne, with the Glycogen Storage Disease Type Ia. There are a lot of ways of looking at this disorder where you can't make glucose, but what was important to patients was the fact that they have to take cornstarch every few hours, and there's like a gun to their head that they could go low in glucose at any time. That's the fear. Being able to remove the need to have that drive to starch is what would change the future for them, and that's our endpoint in that program is the reduction in cornstarch usage, the ability to be free of the fear of needing to take cornstarch. Two examples of how we use patient experience to design and develop our products. Now, as we're growing, now we're a company that's both driving revenue growth and driving clinical data, and we have to do it in a very operationally efficient way. In the current environment, it's also necessary to make sure we're focusing on really high-value drivers, the large pivotal programs, and trying to leverage as much our current pipeline investment in people and infrastructure as well. I'll talk a little more about our revenue growth and data generation here in the next couple of slides. You know, reaching and driving revenue growth, we've built out a global commercial organization. The truth in rare disease, if you really wanna capture the value of a product, you do need to become global to take the full efficiencies of gains that happen by being one company managing globally. You can see now we've covered North America, South America, Europe, Turkey, and Mideast through our loan or through distributors, and we've just added a Japanese subsidiary as well that's now gonna launch our commercial products there. We also manage compassionate use in other territories 'cause as a rare disease company, it's imperative us to consider the needs of patients wherever they are. We have to run the business and do that well, we also need to do it in the right way. If you have the privilege of being a rare disease company, you must take the responsibility too. Now what we've done since the launch of our first program in 2018, it's gone to now what we predict this year to be between $425 million and $450 million in revenue, which I think starting from two people in 2010 to be talking about, you know, mid $400 millions of revenue is a tremendous success for the company in terms of commercializing our programs globally. If you look at our use of cash, last year was a peak year in burn. We used a number of cash investments related to the GeneTx acquisition, a company we bought that involved with the Angelman program. We also bought a license into Evkeeza product. Thirdly, we built out our manufacturing plant, which is now completed. This year, we expect our cash use to move down, OpEx cash use in operations to decrease actually from last year, as well as our expenditures in one-time CapEx investments. So we expect net cash use in operations to be well below $400 million. That's part of also we've done to tighten up the operation and really be smart about our choices in how we run the company. Now with... As a mature, integrated company now and growing revenue base, we're in an important place for our future. We spent a lot of time trying to look at how to increase our leverage, how to improve our operating efficiencies. Being global commercial and having more products in play definitely starts to add to gain. As you've built that out, you can now utilize that resource and get there. The genetics acquisition gave us an incredible value in the Angelman program, giving us full control of it and running it, and we'll talk a little more about Angelman in a moment. The gene therapy manufacturing plant was a big investment. Now that's done, and now it gives us an opportunity to really take control and run and control the cost of gene therapy manufacturing to set us up as a commercial gene therapy company. We have looked hard at managing headcount growth as a company that has grown and making good choices, putting our priority programs first as we move forward. Key upcoming catalysts, I won't go in detail. I'll note that we're gonna talk a lot more about osteogenesis imperfecta and Angelman programs today. I will note that for the gene therapy DTX401, did achieve phase III last patient in, and that puts us closer than have a time clock of a 1-year study, which would be the end of the year, early next year, when we expect to see data for that program. The seven one program is enrolling, and we're pleased with how that's going, and that should finish enrollment this year. The three oh one program is just beginning. Let's talk about UX143 Setrusumab. We haven't spent as much time talking about it, perhaps the street hasn't asked a lot about it, but I wanna highlight to you, I think this is our highest value program, and I actually think it has the strongest data, and it's I think the highest probability of success. I think it builds on our expertise with Crysvita and our knowledge of bone, rare bone diseases. 90% of the KOLs for osteogenesis imperfecta are aligned with our XLH, we're well-positioned commercially to do this program. Now we got into osteogenesis imperfecta through a partnership with Mereo, the disease that they're treating is actually three types of osteogenesis imperfecta, at least 60,000 patients. What I would say to you, I think it's significantly more patients than XLH and really with a higher unmet need with no approved products at all. What we like about the anti-sclerostin antibody Setrusumab is it has a wonderful mechanistic 1-2 punch. It recruits osteoblasts to become bone cells, and those bone cells will land where bone is needed, where the bone is weak. They then will induce those cells to start making bone. To recruit cells to make bone, to drive them to make bone, it's a perfect answer to the question of weak bone and what they need. What we've shown and they've shown, a number of studies have been done showing that when you give anti-sclerostin antibody, you reduce production of bone. You can see the little red spots in the bone. We're increasing bone in the middle of the structure but also around the surface of the bone. This in the long run will create strength by having both the fibers inside as well as on the surface being strengthened. The mechanism is really the right one for what you'd wanna see. If you look what happens in osteogenesis imperfecta model, you can take an animal that has sufficiently decreased bone mass or, and bone weakness, and with an anti-sclerostin, you can actually take that mutated animal and give them essentially normal bone mass and normal strength. It essentially reverses the impact of the mutated collagen in these animals, which is I think a powerful mechanism. It tells you that what we're fixing is the real problem, the fact that the bone is not strong in these patients because of the reaction to the mutation. By restoring that production, we're able to get this to move forward. If you look at that compared to, for example, bisphosphonates, with Setrusumab, you see improvement in bone mass and improvement in bone stiffness and load. When you look at the bone mass improvement that you see with bisphosphonates, you get that and move the mass improvement, but you don't see the same improvement in strength 'cause the bone is not being put down where it needs to be. That's a distinct difference with bisphosphonates. The bone is not put down. It's just kept where it is. It's not laid down where it needs to be. That's why an anabolic agent like Setrusumab is the right kind of solution for an osteogenesis imperfecta patient. What happens then in real patients? The study that Amir conducted, the ASTEROID study, showed that lumbar spine bone mineral density shows a very dose-dependent response, a very strong bone mineral response. A 90% increase in bone mineral density is double what's been seen with any other OI agent ever before. It's a very profound. If you look at the radius failure load, this is actually a calculated measurement of the structure of the radius, that the strength improvement is predicted to be a stronger bone. The amount more bone there is actually done in a way that improves bone strength prediction, and you can see a strong statistical significance to that. We think what we see in the animal models is replicating in the humans. This will improve bone mineral density in the effective way and improve bone strength in OI. The program right now is in a phase II/III study. In the phase II part, we're optimizing the dose. We've learned the dose of 20 that works in the adults very well. We just wanna optimize for children to see whether the children might need more or not. We believe children, though, in all the experience we've had in bone diseases, they respond better and faster than adults. We expect to see even better results in how Setrusumab will work in children. In addition to the phase III study, which we'll be initiating then for that program, we have a second phase III study in young patients, the most severe patients with fractures, and which will be another randomized study, another opportunity to show how Setrusumab will be better than a bisphosphonate in a very severe population of patients whose bones are probably gonna be the most rapidly responsive. I strongly believe that this product is the type of product that will be transformative for OI. It's just doing the right mechanism in the right population, and we're excited about the potential, what we see for Setrusumab going forward. Now let's talk about Angelman. A lot of people wanna talk about Angelman. We picked up this exciting program, it's now been 2 and a half, 3 years ago, and it came out of the blue for most people. Why would we work on Angelman? At that time, we were really intrigued by the science that had come forth by Dr. Dindot. That science told us about this disease locus, the Angelman locus. Angelman itself is a devastating developmental neurodevelopmental disorder. It's caused by a deletion primarily in most patients of a piece of one of the chromosomes, and that deletion then doesn't allow the expression of an important protein. By using an antisense oligonucleotide, we can turn on the father's copy of that chromosome and allow UBE3A to be produced. The science that they discovered was very interesting, and Dr. Scott Dindot, I think, had a better insight into this whole regulation. Normally we wouldn't go into a competitive space like this, but because what they had discovered, we felt there was a distinct edge in what they were doing, and we had confidence in the work they were doing. We've announced the data originally from 5 patients some time ago, and I'll tell you, I'll just summarize where we are. We've been treating some more patients of Angelman syndrome with the deletion type here in a phase I/II study. There's 4 monthly doses and 2 doses that are given every 3 months, and we've been titrating to different levels of load and trying to move up through the dose range to find the right balance between safety and efficacy as we move forward. We announced some data later in July. I'll summarize some of that data and give you an update on where we are currently. Now, some of the data, and I won't go through all of it, don't have time, but the receptive expressive communication results in the Bayley score were actually most profound. I've studied the Bayley in a lot of different diseases. I've never seen the Bayley score change. Open label, randomized control, it doesn't change. It's a very rigorous quantitative tool, and we saw in 6 out of 9 patients with improvement in receptive communication. What this means is the patients were able to hear instructions and follow instructions, respond to their name for the first time, and these were very important for parents. If you look at what matters to parents, communication is the top issue with these kids. That improvement in receptive communication with some patients also included expressive communication, the ability to either to make sounds, noises, or express their wants. The commentary from the families that this was very important to them, very exciting to them. When you look at natural history in these patients, it doesn't change. In fact, the deletion patients have zero change, so over time in expressive receptive communication. We're excited about these results, and these continue in these patients as we've continued treating them over the last year. The other really strong result was in the sleep area particularly, and three of the patients that had in the young cohort that had very severe sleep problems began sleeping through the night. You can see from the quotes how important that is to families. If you have a kid who's developmentally delayed who's up all night, that means you're up all night or someone's up all night. It's very disruptive to the family and causes a great deal of difficulty. The kids now are not slept, in the morning they are not well slept either, they're irritable and difficult and have maladaptive behaviors. Sleeping actually becomes a really big deal, and it's one thing we've seen the drug do very well is a change in sleep patterns. The patient is able to sleep normally and wake up appropriately. With the safety profile, we've been now treated 23 doses in the new phase II study. Loading doses range from 2-10, maintenance doses in the range of 10-14 now, up to 14. We have 10 patients with almost a year of exposure and five patients well over a year of exposure, a lot of patients. We've had one additional AE of special interest, which is the lower extremity weakness. This is similar to what we saw before. This patient had gotten a 4th dose loading at 12. He was a 17-year-old, a very small 17-year-old of 46 kilos, and he had a very severe scoliosis. He was an unusual kid. He had moderately every AS protein and some difference in weakness in walking, but that seems to resolve very promptly. He's doing fine now. We've had no other incidents of this lower weakness, but we continue to dose patients and continue to work toward progression of the program. If you look at the whole story right now, we haven't put out a major new data update. We will do that later this year. What we're seeing is very encouraging signs of clinical activity. We're seeing clinical responses at these lower loading doses, and we're continuing to do that dose escalation through the maintenance doses. We'll add some more patients in an expansion cohort, which will help give us more information about what the safety and efficacy looks like in the middle doses. What we're seeing, though, I think is very encouraging clinical activity. The Bayley score type of changes, improvement of sleep, improvement in maladaptive behavior. Some of the kids have a lot of maladaptive behavior problems, including things like using a fork or walking in more stable gait and better gait. We're encouraged talking to investigators and parents. We've talked to the parents about how important these changes are, and honestly they are driving to the clinic and getting lumbar punctures every three months, many of them for quite a while now. It's a very worthwhile thing. Now from the original five patients that had a lower extremity weakness problem before, they've all wanted to get on treatment. We now have 3 of them back on treatment. 2 have flown to Canada to get their treatment, sort of reverse medical tourism, yes. They're doing well. They're gaining ground again and very excited about how they're benefiting. They've had no weakness. We had 1 patient that we approached FDA, the investigator approached FDA for early access program. The FDA granted it, including a cap of 7.5 milligrams, which was higher than we had before. That patient, after 1 dose, actually within a couple weeks started sleeping in through the night. You can see here the note from the mom. The first time they got 1 dose of drug and they were sleeping through the night, the whole family was excited. The kid, you can see what she talks about, following directions, learning, playing with his kids, friends. He changed, and they lost all that. They were like, she wrote me this impassioned letter to please be a hero for our kid, get this kid treated. They wrote to the FDA with that. The FDA agreed to let them get dosed. They're back on track, they're excited. I'm really pleased that even at the lower doses, they got the sleep effect immediately, and the kid's feeling and doing better. I would say to you, they're very unusual, and for me, and I would say actually history, how many times have we ever treated anything and improved developmental function within weeks to months? It just doesn't happen. This is something very special. Certainly one of the exciting things certainly I've done in my career. We're confident about the value of GTX-102 and its ability to change the future for our Angelman. We're working through the dosing, and we'll put out data more this year about where we are on that program and how we're going to head to phase III. Next steps is to get the FDA to harmonize and let us get the protocol open for expansion in the U.S., expanding, of course, ex-U.S., which are ready to start, and later in the year, phase III planning. I'll touch on the gene therapy franchise. I won't go into detail. We have quite a lot, but it is an important area. While gene therapy's had its ups and downs, the truth is, regardless of what the ups and downs are, the gene therapy has the ability to do something we couldn't do any other way before. That's not going away. That problem, the gene therapy solution, is a solution to things you can't solve any other way. We have a number of programs I think will be the first-ever treatments for these diseases, and I think will be profound, a profound change for the future. I won't go through all of these, but there's 4 programs and pivotal studies. We'll also have an IND this year for our CDKL5 deficiency disorder and an early-stage program for Duchenne as well. If you look at our pivotal programs, GSDIa and OTC are the ones we've acquired with Dimension originally. GSDIa is actually phase III is fully enrolled now, and it's gone well. The phase III for OTC is beginning. We acquired the MPS IIIA gene therapy from Abeona, and we're going to be talking to FDA about how to get to Accelerated Approval. We think it's time for the FDA to change their attitude about Accelerated Approval. While we can monitor those patients and show that they're getting clinical benefit, I think it's time to change the future for gene therapy and for this disease and get Accelerated Approvals to be the order of the day. It shouldn't just be for Alzheimer's. It should be for these type diseases where the biochemistry is even better and more precise. This is the right way. We've always been an advocate for change and improvement in what we do in regulation. The Wilson disease program is moving along very nicely. We'd expect by mid-year to have enrolled all the dose cohorts. We'll be coming to data fairly soon. We're excited about that. One thing I'll say about Wilson disease, some people have told me, "Hey, his KOLs are fine." They're not fine. KOLs don't change the problem in Wilson disease. The problem in Wilson is copper distribution. The toxicity is part of the problem, but copper distribution has failed, and we don't know what the truth is, what copper distribution done correctly in Wilson disease will do for that disease until we do it. What I'll tell you, it's one of the ones I'm sure will change people's mind of what really is going on in Wilson disease when we get there. We're excited about the Wilson possibility of changing the future of Wilson's disease patients by fixing the problem, not just sopping up the extra copper. Finally, the Pinnacle platform and our gene therapy franchise. With the Wilson program, we are using the Pinnacle PCL platform. The great value of that is it reduced the cost of making the gene therapy by 80%. It also allows us to go to bigger scale and to be very efficient. We've taken the platform, we've now built a plant that will run that platform and can run HEK triple transfection as well. The plant will be able to take on a number of our programs, will give us the flexibility, quality, cost control to allow our gene therapy franchise to become true commercial programs, to be good opportunities both for patients and as a business. Foundation for value generation. I think if you think about where we are, it's what's the next step that's gonna drive us forward? We like to put this forth to you that any one of these 3, osteogenesis imperfecta, Angelman, or Wilson, could drive us forward as a company, being a major driver of value for us, and yet we have all 3 coming forward. I would think people should think hard about the diversified strength of the company and how many ways we have to grow, and the fact that we have an established base of four products also already generating revenue. I think it puts us in a very unique position of value creation that you don't see too often in the rare disease industry. We are trying to lead, and we are leading the future of rare disease medicine, both in what we do in drug development, but also in what we do in policy. We have one of the most robust pipelines, especially advanced pipelines in rare. Broad commercial global footprint generating revenue, and very effective, strong clinical execution with a high success rate. I think more important than anything we have, we're inspired by the mission and the responsibility that comes with the privilege of being a company developing rare disease treatments. Thank you for this, and time for a chat. Is that a problem? Sure. Thanks, Emil. Just as a reminder, 3 ways you can ask a question here. You can send it in a digital book, you can email me, or if you wanna get bold, you can raise your hand, and we'll call on you. Probably, the most common question that we've gotten since, Mm-hmm. the update, Friday after the close, as well as the disclosure of the slides, is on the adverse event of special interest in Angelman. Yes. Maybe you could expand on what exactly you were seeing there and how you think about this AE, like, as you're dosing now more and more patients at higher loading and maintenance doses. The, the case is a little bit complicated, and, you know, I probably wouldn't have picked someone with scoliosis for a lumbar puncture type treatment. We'll have that discussion with the investigator. The, the truth is, when you have scoliosis, it's hard to do the procedure. What we're doing with the procedure is we're putting the drug in the lower back, right? In the lumbar space, and we're putting the patient in Trendelenburg, so the drug moves to the north, and we put a flush drug to move it along. Part of what we know is the genesis of the problem is it's too much of a high concentration of drug locally near the nerve roots, right where you put the drug in. That's sort of the genesis of the problem. Highly localized irritation. It's a very simple solution. I think in this case, the solution didn't work. I'd hate to make conclusions about the overall program from this rather unusual patient. We have a lot of people getting 10-14 milligrams of drug right now without any issue. We think we have to manage the process of how it's done, but we don't think it really changes the overall outcome for our enrollment. Questions from the audience? Emil, I think you want some Setrusumab questions based on your comment on the podium. I'll ask one. Can you remind us of the key biomarkers of focus and what level of benefit you'll be looking for in the mid-year update? Well, in the mid-year update, let's be clear. We already know a dose. That 20 mg per kilo gives us an excellent bone mineral density response. We already have that in hand. The only question we wanna know is, if you're 5 year old, not 25 year old, would you might need more drug in order to get the same level of exposure and pharmacodynamic effects? It's about tuning the dose, not about defining the dose. To tune the dose, we wanna look at what P1NP. P1NP, for those who know what it is, it's the little pieces of peptide that get cut off of collagen. Your body makes collagen in a form with little tags on the end, when the contractor lays it into your bone, it chops off the tags, and they slot in, and they form fibers. When you chop off those those little tags, they end up in your urine. Now you can look at those tags and tell you how much bone is getting laid down by how much collagen being laid down. That's what we're gonna look at. If we see a 10% or 15% improvement, it doesn't matter. I think if we're looking for in the young kids, if we see that the PK concentrations are not as high at the 20 mg dose and we're getting them more where we wanna be and the P1NP is 50%, 80% more, then I think that would tell you that there is a meaningful benefit in the younger patients to give a higher dose. We don't expect that to be needed for the older patients. We're including them in this test just to show that they, we have topped out on the effect and based on everything, well, we think we have. That's kind of what we're looking. We'll use the P1NP. Now we know from the data that was shown, it's a very nice data set, that P1NP actually will predict bone mineral density in the patients over the year. So you can look at the first couple months and know what their bone mineral density pattern is gonna be. Even though bone mineral density is building over an entire year, the first couple months of P1NP will give us an adequate predictive value of what's gonna happen with bone mineral density. We actually have a question in the, in the portal related to Setrusumab. Mm-hmm. Which is, will the drug work differently in cortical versus cancellous bone? It works on all different types of bone, frankly. That's partly that picture I showed you. It works on the surface and within the middle of bone. If you look at the, in fact, the one thing you have to understand when you measure bone mineral density, it's often easiest when you're looking at, for example, lumbar spine to see the bone mineral density improvement. When you look at long bones, the bone mineral density is concentrated around the outer, the shank, you know. You don't see the bone mineral density change as much. The percent change isn't much, but it's 'cause it's on a long, thin shaft. When you look in the vertebrae, and one of the reasons we look at the vertebrae is they have a lot more individual spicules of bone that you can detect that change. The thing I would say to you is whether it's one bone. It's really affecting both. It's just the way you look at bone mineral density is different between those types of bones. What I would say to you is very important is that the lumbar spine is actually very important in OI. People think about bone breaking like the long bones, but your long bones you can always fix. If your vertebrae collapse, there's no fix for that. With these kids with Type III and Type IV, their vertebrae are actually collapsing as they're kids, and they shrink, and they end up causing nerve compression, back pain problems. They end up in wheelchairs. That's the devastation of Type III or Type IV OI. The lumbar spine benefit in that type of bone is actually extremely important to keeping their spines long and keeping them from having the kind of compressions and loss of function that I think is devastating. That's why treating the really young kids like we're doing in that study could be very important to be able to take a two-year-old and change their future and be able to show that as early as we can in the in the development and commercialization program to show what this can do to change their bone future in a bone type that you can't, you can't put a cast on it. You can't fix it once it's messed up. Question from the audience? I guess I'll continue. Emil, can you walk us through the rationale for why you're guiding Crysvita a little bit differently in 2023 than you did in 2022, where we only got rare territories, and this year you're including the EU royalties as well? The Crysvita revenue story is a little bit complicated because of different territories and how the revenue is being addressed. For accounting reasons, EU royalty revenue is still considered revenue. It just becomes non-cash. In the U.S., we have a profit share agreement which continues through April, then it shifts to a royalty stream, which creates confusion in how you're doing it. We're approaching the revenue as if it's the same, but we're not actually. We also sold a piece of the revenue to OMERS, which is still being counted, so we're kind of making it apples to apples, so you can compare the revenue over time. I don't think it changed anything. It just changes perhaps how you're looking at the cash changes are. I think it allows you to see what. how our revenue stream operates within the GAAP. It is a little bit different because we'll switch over. What I say to you and people wonder, well, are you losing the product in the U.S.? We're not losing the product. What's happening is we're not becoming the lead commercialization partner. Our partner will become the lead commercialization partner, and our revenue stream turns into a royalty stream. It's, the revenue numbers are almost the same, essentially. Through a transition agreement with our partner, Kirin, we are now actually gonna stay commercial in the field longer and split those expenses with them. That we'll continue that transition to ensure that we actually have... We'll actually have an increase of field personnel, 100 in the field at Crysvita overlapping to ensure that the handoff is strong and that Crysvita doesn't miss a beat in this transition. Questions from the audience? You talked a little bit about the cash use of operations and-. Mm-hmm. Expenses and that being less than $400 million, I believe, right? How do we think about the next couple of years given your development program? Well, I think what we're trying to signal is our peak burn is behind us, and it should be shrinking because each year our revenue growth will start bringing our cash use down. We're heading on a trajectory of decreasing net cash use, going forward. With the 4 products alone will take us to close to profitability, with additional products that will take us over the top. It'll take us most of the way there. We're just trying to signal that we're gonna be disciplined about spending. The fact we have increasing revenue doesn't mean we're just gonna continuously linearly increase our OpEx spending. We think we can manage it at this level, keep our headcount controlled, and operate with our focus on our highest value programs. I've got a email question that kind of came into my inbox, which is, at what point will you have gotten, Basically, talk to us about how much data you need to give us guidance on when we could get the next 102 update? Like, what are you. Yeah. On Angelman, we wanna make sure we have enough data to make a good conclusion, and we wanna get some more data on patients loaded at a higher dose level than we had before. From the last update, we had patients at a low dose loading level that were now put onto maintenance. Since that time, we've added some dosing at a little bit higher, but we've added what I would call sentinel cohorts, just testing it out to see how it is. We wanna now expand that and add enough patients, so we have enough patients at a particular loading regimen to be able to say to you conclusively what that looks like and not to be talking about one at a time patients. We're gonna be doing that. Right now, we said we're expanding the study at a particular dose load level for ex-US starting in the beginning of the year, and we're looking to get the US to open and allow us to do that in the US as well. We expect to add about 40 patients, we've said we would potentially talk about our results before all 40 have completed six months. It could be a fraction of those, at least enough patients to give you a substantial feel that we are on track. We understand what the dose should be, what the load is, and what we're seeing for efficacy. With that update, we'd wanna provide you analysis of how the change in efficacy compares to control or to, or to natural history controls in a very precise way and to give you confidence around what the magnitude effect is and be able to interpret it, as well as understanding what would that mean for a phase III program and design of the endpoint and powering the study. Any final questions? Great. Thank you, Andrew. Thank you.