Ultragenyx Pharmaceutical Inc. (RARE) Earnings Call Transcript & Summary

All right. Good afternoon, everyone. Welcome to the 40th Annual JPMorgan Healthcare Conference. My name is Cory Kasimov. I'm the senior large-cap biotech analyst. And it's my pleasure to introduce Ultragenyx and the company's CEO, Emil Kakkis. And please note that following the presentation, we'll move directly into a Q&A session where you can send in your own questions via the conference portal, and I'll do my best to work these into the conversation. So Emil, thanks, as always, for joining us. And let me turn things over to you for an update.

Thanks very much, Cory. Good to see you and good to see everyone. I know it's been a busy day and a lot going on, but I'm happy to give you an update on Ultragenyx and where we are today. If you go past the cover slide, you'll see our legal warning regarding investment in Ultragenyx. And going to the third slide, we'll talk about our recent highlights. So we've had a lot of news recently in a few different things. One, we preannounced our Crysvita revenue. I'll talk a little more of that in a moment. We exceeded our guidance that we set early in the year, despite being a COVID year, and we're pleased with our progress in Dojolvi as well. We'll talk about that in a moment. We also announced a new product addition to our commercial franchise, Evkeeza, in a partnership with Regeneron. It's a strategic around rare diseases. We'll be commercializing ex U.S. Evkeeza. And I'll talk deeply about that program and the value it brings to Ultragenyx going forward and building our commercial franchise ex U.S. Finally, I'll touch on the Angelman update, which are showing the low doses and the improved and the safety, continuing well in our update and give you a little more depth into that. And I'm sure, at the end, we're going to answer more questions on all 3 of these areas. So on the next slide, let's talk about the revenue story. We hit our revenue and we're coming into the $191 million, $193 million range. As you know, Dojolvi now getting $38 million, $40 million revenue, which was, I think, an excellent performance for both programs given the tremendous impact that COVID has been having on things. If we look forward to our guidance next year, substantial, greater than 30% growth both in Crysvita in all of our territories as well as Dojolvi. And I think it shows a very strong commercial execution really in the face of COVID as well. But we're pleased to see how the products are getting accepted and we're getting traction in Latin America and elsewhere. We have a strong capital position with now $1 billion in cash. We're in very good position to execute on our priorities and move forward. Now let's talk about Regeneron collaboration for Evkeeza. We believe this is a valuable deal for Ultragenyx. It makes good sense for us to do it. First of all, it's a potent late-stage product. This is an antibody that has a very profound effect, and I'll show you that today in a second. It's first-in-class with the ANGPTL3 mechanism, which I think is the optimal mechanism for affecting HoFH or homozygous familial hypercholesterolemia. That mechanism really is the best mechanism toward rerouting lipid out of the bloodstream into the liver where it's supposed to go. And so we think this will have clinical impact in the long run for these patients, and we think the data were very strong. We have a commercial infrastructure ex U.S., which Regeneron does not. And therefore, it leverages that infrastructure in both Europe as well as Canada, Lat Am and elsewhere, and including initiating a Japan entity for us, which will commercialize both Evkeeza as well as Dojolvi. So we think it builds in our commercial infrastructure to ex U.S. And finally, as a strategic partner with a very strong company. If you're going to pick a company to make antibodies and we do partnership around antibodies, Regeneron is certainly one of the top-tier companies in the space. And by doing that partnership, it allows us to have 2 antibodies in our portfolio which really diversifies our portfolio, not just having genetic medicines, but having what I would call traditional biologics with their risk profile. And something that's late stage like this really adds into the strength of the building revenue story for the company going forward. So we're excited about the deal. We think it's the right thing. We know it was not expected by some people, but we've done a good job in picking good assets and finding ways to grow value for the company. And I think this is one key piece of that story. Now on the next slide, you see comparing Regeneron with Ultragenyx. Basically, they developed a product, got it approved in U.S. and Europe. And our job will be, and they're going to make the product for us. Our job, mainly get it approved in other territories and the launch and get reimbursement, of course, for the product. Those are the main roles that we have. There may be other indications for which we could share additional expenditures if we want to add on those indications to our territory. But we think it's a very reasonable deal, cost. If you think about a traditional novel biologic for a rare disease at this stage of development, we're very pleased with the terms and we're happy we're able to do this deal with Regeneron. Now let's talk on the next slide about Evkeeza itself and the mechanism, which I think is really important. We strongly believe in potent drugs for bad disease. And HoFH, despite all the studies and what work has been done in this disease, the true homozygous null patients still don't have a great treatment. And this drug will be one of the first ones. And if you look at the mechanism, your body makes VLDL normally. And then they'll get converted by the lipase that's circulating. That lipase converts it to LDL. And what these patients can't retake up LDL in the liver because the LDL receptor is gone. And so what ends up happening with Evkeeza is you block the conversion of VLDL and you end up making more VLDL remnants, which now are bypassed and taken up by the liver by an alternative, the VLDL remnant receptor. So it ends up at the correct place just through a different pathway by tweaking the system and diverting essentially the lipid. So we think this is an excellent mechanism. And remember, the ANGPTL3 target was validated for humans based on the fact that patients, the mutations there have improved cardiovascular outcomes significantly. And we think it's exactly the right medicine for this disease that's why we're happy to be working on this program. It is a lipid, but we work in lipid metabolism. Fatty acid oxidation defect, by the way, are lipid metabolism. It's also about energy metabolism. All of our glycogen storage and lipid programs are in energy metabolism. So while the call point is different for hypercholesterolemia, most of the centers in Europe and elsewhere are highly specialized and therefore, we can use the orphan model in how we commercialize. And we feel we can leverage a lot of the people that we have and with modest growth be able to handle this new product. We'll also be able to move toward Japan as well. Let me touch on the data on the next, Slide 8. The data were excellent. 49% reduction, very tight error bars. That means everyone responds. I think that's what's the amazing part of how well this works. And if you're a null patient, and you can see second bullet there, 72% reduction relative to placebo. These are massive improvements. And triglycerides also reduce by 50%. So that's an incredibly potent drug, and we think this is going to be transforming for HoFH. We're very excited about the potential. And we did some work and we know from the, if you look on the next, Slide 9, we went and talked to KOLs through a third party, did our own market research to the program and found really very enthusiastic response from KOLs. These are European KOLs who often are not very enthusiastic about anything. But in this case, they were very enthusiastic about this product being the product they want to use for their homozygous patients. So we think this is a great product for a bad disease. The population is around 3,000 to 5,000 in areas. We'll commercialize 1,600 in Europe. So we think it's a good size opportunity for us to build our revenue base as a company and to be able to commercialize with our partner, Regeneron. Now on the next slide, I'll move on to talk about the Angelman program. I won't go too much in the background of Angelman. I think you know it all. We consider the prevalence around 60,000 in the developed areas where we think we can commercialize. I know there have been some recent numbers suggesting Angelman is much broader. It's a neurodevelopmental disease and we're focused on areas where we think we could commercialize. Now let's talk on the next, Slide 11. This is just a summary of the amended protocol. I won't go through all of this again, but this is just the detail of who's getting what in the trial that we're conducting. We initiated treatment in both Canada and the U.K. in Cohort 4 and Cohort 5. And we put out some data recently on those patients. I'll touch on that in a moment. The U.S. group hasn't started dosing, but they're ready to start imminently. So the proceeding, the 2 cohorts are proceeding promptly. In the Cohort 4, the initial 2 patients received 3 and 4 doses, including escalation to 5. DSMB looked at the 2 patient data that was available of the young patient population and determined that it was safe for us to add additional 4 patients. The first of those additional 4 have now been treated and giving us the opportunity to get 6 patients' worth of data in midyear. Cohort 5 is a little bit behind that. Two patients received 2 doses each to date and then will go to dose escalation soon. And we expect the DSMB meeting to be scheduled soon, which will allow us then to enroll an additional 4 patients in that group as well. So both programs moving along well, and we're happy to see how progress is happening. What we talked about for data because we haven't had any, if you look on the next slide, 13, no treatment-related SAEs of any type and no lower extremity weakness whatsoever in these patients. So we're good, comfortable so far. Just not treating them for 4 months would get this problem. And we believe it's never been about cumulative dose, it's really been about acute dose. And so far, that turns out to be correct. Based on the CGI that's been completed in 3 of the 4 patients who had at least 2 doses, we have seen activity in multiple domains, that is for improvement in multiple domains, but we haven't seen 2-plus in 2 domains in any individual at this point, which is why the patients have escalated to the next dose level. That was expected. I've told investors all along our expectations. The first dose level would not stop. Patient would need to go to the second dose level. But we think as we get into these next dose levels, we'll accumulate enough drug to get the treatment effect we saw before. The fact we're seeing signs of change that are very similar to what we saw before give us confidence that, that's true. And the fact we're not seeing the safety event is a comfort. So we guide to having, hopefully, all 12 patients, 6 and 6 is our expectation, we'll get the body of this data through day 128 toward the middle of the year, which I think will be the first substantive piece of data on this molecule that tell us about the safety and efficacy. But we're encouraged so far on the data we've seen. Now let's go on to the next slide. If you think about us as a big company, we've changed from where we were. 11 years ago, it was 2 people. Now we're 1,100 people. We have a global commercial growth that's ongoing with the Crysvita franchise, Dojolvi franchise, Evkeeza as well as Mepsevii. Development pipeline very rich. How many people have 4 pivotal programs, 6 clinical programs that are operating around the world. I think that is special. And we have advanced technology platforms, whether it's the AAV platform or the PCL platform, commercial-scale manufacturing, the mRNA. We're a very complete company now, and I think in very good position from a financial standpoint. If you look on the next slide, 15, you can see that we have a very diverse pipeline. And I would compare that with any company out there with 4 approved products in 5 indications and a diverse set of programs going forward. I won't go through all of these today, but just the visual of that is we have created an extremely strong company from the standpoint of development of rare disease indications in a variety of modes. And on Slide 16, you can look at those different product pipelines incorporating or being part of 3 therapeutic areas. The bone endocrine space is Crysvita. And setrusumab is now the one that's going to come and fill. And we continue to look for more bone franchise targets. In metabolic, we have, of course, the early programs in Mepsevii, Dojolvi, now Evkeeza, but we're adding on 2 gene, 3 gene therapies as well as an mRNA therapy in that program. And if you look at the CNS area, Angelman is kind of the lead program right now, but we have some other pipeline programs coming in. And we'll be building out CNS/muscle, which I think is an area where there are a lot of opportunities. But that gives you an idea of how it looks from a therapeutic area standpoint. Let's go on and talk about setrusumab, which is the next slide and the next slide after that. Setrusumab for osteogenesis imperfecta, I think, is a really important indication for us. And the reason it's important is a follow-on to our Crysvita franchise. Osteogenesis imperfecta is a more severe disease even than XLH. The demand for treatment, we think, will be even greater than XLH. And the current treatment with bisphosphonates are a modest benefit to these patients. And we think there's a lot of room for improvement. Setrusumab is an anti-sclerostin, and we think is an excellent opportunity to change the future for our OI patients. And we think the data in hand have told us that what's unique about anti-sclerostin as a mechanism does 2 things. It recruits osteoblast to become osteocytes and induces them to produce bone. Those features will allow you to strengthen the bone of patients. And that is what these patients really need, not so much blocking the resorption. They need to strengthen the bone. And I think because of genetic defects in collagen, the loss and breakdown of bone, the failure to make new bone is what's really causing the weakness, the response, the maladaptive response to the defect. And we know in animal models that you can actually normalize bone strength simply by turning on anabolism, which will build strength right in the bones where the weakness exists. That's how the system works for bone. So we think anabolism, building bone is the right way to go with OI, and that's why we're excited about anti-sclerostin. If you look on the next slide, the data brought forth by Mereo in the ASTEROID study. I think it's already given us the information we need to know about the drug's efficacy in OI. 90 patients studied, but it's very clear 20-mg per kilo dose is effective and gave bone mineral density across the bones that were important. But I'd like to focus on the lumbar spine, where it was in the 8% to 10% range, which is about double a lot of anabolic agents. The spine is a place that degenerates in type 3 and 4 particularly that make them ultimately wheelchair-bound and inherit terrible pain. By preventing lumbar spine and creating strength there, I think it's going to be one of the really important things in the long run for OI. If we can change that paradigm in these patients, particularly treating younger children, I think you'd have the potential to really transform future of OI. And among all the mechanisms since we did this deal, I am still confident that the anti-sclerostin mechanism is the best mechanism. It's doing the right thing and it's doing it in the right way. And we feel comfortable the data we have on hand puts us in position to have an important outcome with osteogenesis imperfecta. The next steps now is get the study. The Phase II part of the study will treat 40 patients 20-mg dose. We know it's good. We're going to look at 40 as well. We'll compare the 2. And we'll look at young children, too. It's possible that young children may need a higher dose. We've seen that in many other antibody programs, including our own Crysvita program. We want to make sure we don't leave any efficacy on the table that we couldn't take advantage of. We'll look at between 20 and 40, come up with a dosing algorithm off the first 40 patients using their drug exposure as well as their biomarker, pharmacodynamic effects and then employ that algorithm between 20 and 40-milligram dosing to proceed ahead into the pivotal Phase III trial. The first part of the trial starting imminently, and we'll collect data, and we expect to see some of that data here in the second half when we'll be able to initiate the Phase III. So that's setrusumab. Let's go on to the next slide and should go on to Slide 22 to talk about gene therapy. I won't go through the overview of the gene therapy program. Obviously, have a number of programs, a number of partnerships, but we also have the producer cell line platform. And I think what you're going to start seeing more and more as people talk about manufacturing, manufacturing costs, manufacturing quality and reliability, and I think the PCL platform we have is clearly the superior pathway. We're moving that way, and I think you'll find more and more people moving in that direction. And therefore, we will have, I think, the most advanced system for a large-scale commercial AAV manufacturing going forward. And that will put us in good position as a company in our gene therapy business. Now if you go on to the next slide, talk about AAV8 for glycogen storage disease. That program has been moving along for a while with great data. It's hypoglycemic caused by inability to release the glucose from the liver. We provide the enzyme through the gene therapy so they can release glucose and now start to control their own glucose. Our vector involves a normal promoter region of this enzyme G6Pase. That enzyme regulatory region means that your body will send signals to the liver and the transgene will respond to those signals as they normally do. This is an important part of increasing the sophistication of gene therapy to not just pump a gene in and make a bunch of whatever, but in fact, to create a system that's restoring normal regulation that's listening to signals and responding appropriately. We think that will be important in G6Pase particularly. If you look on the next slide, this shows the data over time. We showed that there's a dramatic drop in starch requirements early on and then steadily it gets better and better over time. Part of this is the body needs to adapt to a low starch regimen. It needs to produce less insulin. They're hyperinsulinemic, start to alter other hormones. We see those hormones changing in the second year to the third year, but we're quite comfortable that in the first 48 weeks, we show the differential between treatment of the gene therapy or placebo. The Phase III program on the next slide, basically, we've got an agreement, understanding. There are probably some details we'll work out with the analysis of the data, but we'll be doing a Phase III design and it's 48 weeks, 50 patients, 1:1 randomization. The primary endpoint will be the reduction in cornstarch, which I would call oral glucose replacement therapy. The amount of reduction in exogenous glucose replacement therapy will be essentially the endpoint. And it's more than just starch, that is the gun to the head of the patient. The fear that if they don't take it, they're going to get sick or they're going to get crashed and potentially die. That's what goes away when you don't have to take oral glucose replacement therapy. You now know your body is doing it for you and you can reduce the fear, the gun to the head that really affects these patients. We'll certainly have other endpoints that give us more clinical input. Now let's move on to DTX301 for OTC. That's an AAV8 for ornithine transcarbamylase and urea cycle defect. We've been studying these patients for a while. These patients can't basically take ammonia and convert it into urea because of a break in the first enzyme in that process. And therefore, we're trying to replace that enzyme in the liver, the liver being the primary organ that's involved in ureagenesis. Now I'll move on to the data we have so far. We've shown a very nice response in a number of patients at the higher doses. We had less complete response at lower doses. But the higher doses, we were getting all patients responding and showing significant reduction in ammonia when that was present or improvement in their ureagenesis. Several patients were able to get off all drugs and diet, and this put us, showing that this was a clinically meaningful effect. We did do prophylactic steroid cohort. Both patients were dosed, doing well and demonstrating a response. We're looking at the second patient. It's been hard to do these responses and evaluate them because of inability to get patients in related to COVID, in general. But we're pleased with how that looked, and we are working with prophylactic steroids in the Phase III. So Phase III study is also 50-patient, randomized, controlled trial. It's a little longer at 64 weeks, which would give us a little more time to look for the removal of drugs, which is one of the co-primary endpoints. So we'll look at 24-hour ammonia and then the reduction in the drugs and control as the co-primary endpoints. Obviously, if we reduce ammonia but can't reduce their drugs or diet, then we haven't done very much. So we do need to be able to reduce their treatment dependence in order to show the effect we've given, I think, is meaningful. So this makes sense for this particular disease, and we'll go a number of areas for their co-secondaries. That's in a nutshell. Last part I'll touch on is the AAV9 for Wilson therapy. This is a truncated transporter of copper, and we've shown this to work extremely well in the mouse model to clear up liver inflammation, liver toxicity within just a few weeks and can also induce plasma production in the bloodstream heading toward closer to the normal range. Those benefits, we think, will be very important in humans with Wilson disease. It's a pretty big opportunity, manyfold more patients than the other 2 diseases that we're working on. If you go on Slide 30, this is the basic design. There's 3 cohorts. They are in a staggered start. They are a regimented staggered start. That is we can't go faster. This is a requirement from the FDA for us to safely introduce this drug. They want to make sure it's safe. We don't have any evidence that it wouldn't be, but they want us to be cautious and do this in a staged way, which will push out the time frame from which we get the first data. But we're on track with that program. We started. We've been enrolling and screening first patients and are moving forward. So we're excited about Wilson finally getting there. And we hope to then continue to enroll and this is the basic design for the study. Last thing I'll touch on is 053 for Glycogen Storage Disease Type III. This is our first mRNA product. And the mRNA program is our first of what we hope would be many in which we're able to do enzyme replacement using the mRNA. So the advantage of this is we can do enzyme replacement in cellular compartments in the liver where you normally couldn't deliver an enzyme. In the case of GSDIII, the enzyme is a bifunctional enzyme involved in glycogen metabolism. And that enzyme is too large to fit in a gene therapy vector. Without it, you get toxicity in the liver. What we've shown is that storage of glycogen, which is shown there in the white spots of cells in that picture on Slide 32, you can clear that storage with essentially a single dose in the mouse model. And what you can show, while liver glycogen goes down there on the right, you can also see glucose increases as the liver's ability to release glucose is restored by the fixing of the glycogen problem. We think there's a significant powerful effect. We get very good delivery with this LNP. So we're very encouraged about the potential to have a very important treatment for GSDIII. And if that's successful, then potentially other products as well. So we're on a, currently in that program, Slide 32, we're on a single ascending dose. We've dosed the first patient. We should be able to put out some data on our single ascending dose. Here, we'll see how the trial progresses. And that will tell us a little about how much potency we're seeing. And from that, we'll then decide on what the multiple dose point will be. But it's the first time in man, so we're definitely going to take it slow and look carefully at things. But we're encouraged by what we've seen in animals and where we think the potency of this can be. And so we'll carefully try to find the right dose point for humans, and we'll do that this year. So if you look at our overall picture on Slide, the next slide, 33, 2017-2021, 4 approvals and launches, and we've built out a pipeline and I think have one of the pipelines in the business today. If you think about how many the gene therapy ASOs as well as the traditional biologics in our portfolio, we are very well fitted as a company, both in the breadth of indications that we're studying, the advanced stage, the commercial abilities and the global commercial company we've become. And I think it's a testament that the team has been able to drive along these last 4 years and take first products through and build out a complete and full pipeline at the same time without missing a step. Look at our catalysts here. I think, obviously, if I had to put the size of the font in relation to what everyone is thinking. The Angelman probably would be a 50-point font. The other ones were relatively small. Everyone's eyes are on Angelman. This year, we expect the data from Phase I/II to come out midyear on the first 12 patients. It will be data through day 128. And we'll talk about where we are in the earlier patients that have been treated earlier, how far along they are as well at that point in time. We like to put out data on when we have substantial progress in the program, and we've put out the data we have so far to try to just give people a read of where we're headed, which I think is in good place. I've said that if we have a lower extremity weakness event, we would announce that. So if you don't hear that, that means we haven't had that event. And I don't think we will get it as long as we manage the administration and the strategy we've been doing. We'll also be moving forward in our 053 program. It's a single-ascending dose. We'll have some information on UX143 as well. And in addition to that, the gene therapy should be progressing most of the year through their enrollment. We'll also, of course, be announcing progress on the launches and commercial growth throughout the year. So we have a busy year ahead of us. So finally, as a company, I think we have one of the broadest, most diverse clinical pipelines as well as strong commercial execution as a company. And with the Evkeeza adding in giving us another product ex U.S. to work with in that deal with Regeneron, I think we're in a really good position as a company to generate growing revenue and heading toward a potential launch of multiple, larger programs going forward and build, I think, one of the best rare disease companies in the business. That's where we are today. This is Slide 35. So that's it from the top at this moment, and we're okay, ready to start breakout. Maybe, Mardi, you can come on?

Perfect. Well, thank you, Emil. And just a reminder to our audience, you can submit questions into the portal as well. And we do have some in here and no surprise, Angelman. So I guess let's start there because I know this is what everybody wants to talk about. And we have a little over 10 minutes here for Q&A.

So I guess, Emil, just to sort of level set here. What is this initial Angelman update since you restarted, due to your overall confidence in this program or is it really unchanged because this is exactly what you were expecting?

Well, it is exactly what I was expecting. And I had confidence before that lower doses and that managing local exposure would affect this so. But I do think it's important to actually have data saying you can repeatedly dose at this level, not see the problem at all, not even any weakness and be completely clear of that problem and without the irritation, inflammation. So I think it is reassuring, but I was confident we'd be good. But I think for investors, they'd rather see data than just CEO confidence. So for them, I'm sure it should help them understand, hey, you can dose this drug and not run into that problem. Even if you give 4 doses of it, you won't see that problem. So I'm encouraged by it. And I think it puts us on track to getting the dose into the therapeutic range and finding a place where this drug could be used and that the prior experience, shooting past the therapeutic window I think was unfortunate, but I think we're in a good position now to get to that answer. And by midyear, you'll have an answer for it.

Right. And is this enough patients worth of data to be confident given that you saw it in basically every patient before. Now none of them this time around? Is that all the evidence you need in terms of just getting past this one safety risk?

Well, if we can get efficacy that's on par by accumulating the drug in smaller doses, we get efficacy on par and not see the safety event, it tells you that you can differentiate for dosing that are effective in doses of constant safety. And that's the key thing, which tells you there is a therapeutic window. If we can do that by midyear, then I feel confident the drug has a future being able to find a window for patients. So I do think that, that is what's important here. I do think, though, that 12 patients is not a lot of patients either. But since we had 100% have it, if we have none have it and we get that dose, I think it tells you, you can find a window here for at least a majority of patients. We will expand the study with the cleared dose and get more information going forward before we initiate Phase III because I would like to see 40 or 50 patients treated with drug multiple times to get confidence that we can go into a Phase III. And our hope would be to expand the trial at the new found safe dose, continue treating those patients and learn for them while we negotiate what Phase III would look like in parallel with the regulatory authorities.

Okay. And then next question is around the update we'll get at midyear and pull on directly out of the portal here. How many patients worth of data will we see and what age cohorts will they be?

So there'll be 12 patients total is our expectation. It should be 6 below age 8 and 6 over age 8. That's Cohort 4. It's the low age. Cohort 5, the older. Should be 6 in both cohorts. That's what we'd expect. We're expecting the older patients to get through their DMC and expand their cohort shortly. So it'll be 6 and 6. It's day 128. At day 128, we'll have the CGIs for the global and individual domains, but we'll also have the Bayleys, Vineland, those other analysis done at day 128, right, compared to baseline. So it will be a whole series of endpoints like we did the last time we released data on this program. You'll get the underpinning data. What we hope to see is that we see something on CGI. We'd want to see that there's support of other data and the other endpoints that cover the same domain, right? That's what we saw before. We'd be looking for reassurance that a CGI score is not just wishful thinking but is actually replicated in the observation of that patient not just by the doctor, but by the psychologist and parent and others who are doing the evaluation. So that's what we'd be looking for at the middle of the year.

Okay. And then another one from the portal is regarding Angelman. Which protocol do you think is stronger or more effective, the U.S. protocol, the 2-milligram start or the U.K. Canadian protocol or is it too soon to say?

Well, I think the U.K. Canadian protocol is what we optimally wanted to do because it includes a dose that's a bit higher that we think will be more important for achieving efficacy and yet still be safe. And we think it also includes the Trendelenburg flush regimen, which we think is a better way to go to reduce local exposure. The 2-milligram dose in the U.S. could work, but its primary purpose is to get us started with the FDA, and they wanted a 10x safety factor, that's why we're doing 2-mg in the U.S. It will allow us to learn about dose effect at the 2-mg dose repeatedly. So it's a fair bit of information to learn. I think it will have some effect in those patients. But we hope with our midyear update to come back to the U.S. and consolidate the programs around a dosing strategy and dosing approach that would be consistent. If the ex U.S. approach looks promising, showing good effect and safety, then we want to take that to the FDA and maybe upgrade the U.S. program to that regimen.

Okay. And between now and the middle of the year, is this a situation where no news is good news at least on the safety front. Obviously, it won't say anything about efficacy but from a safety standpoint?

Yes. What we've said is if there is a lower extremity weakness adverse event, what was seen before, if we're seeing that, we would announce it. If there's something that stops a program, of course, we're going to announce it too, right? So that's if no news generally would mean good news from a safety standpoint. We're going to try to hold off on releasing bits of efficacy data as it goes because I just think that dribbling out data is not fair to the patients. It's not the way to operate. We want to operate going forward in a thoughtful way, get a complete set of data and talk to the investors in a complete way about what we're seeing.

Okay. Makes sense. And then assuming you get supportive Phase I/II data, what do you think next steps would be? What's the path to potential registration?

Well, we think what Phase I/II will tell us as we titrate the dose higher and we'll figure out what's that level where we're seeing safety or starting to see good efficacy. What I want to do is take that dose level and start another 40 patients with that dose level. The purpose would be to see if we can give 4 doses of that dose level that appears to be safe, doesn't constitute problems and verify if we can load the patients up a little bit further and dial up the efficacy once we know that, that dose level is safe. When we expand the study into the 40 patients will give us a preview of what we expect Phase III to look like. We'll do those 40 patients, treating them while we negotiate our Phase III design and power. What we'll do when we get the design together is we'll then finalize what the dosing regimen will be after we treated those additional patients. But we can at least talk what are the endpoints and how we're evaluating it based on the 12 patients worth of data with the agency and knowing full well that we'll get additional piece of data before we actually would initiate a Phase III.

Okay. All right. Another Angelman and then we'll move on for our last few minutes. This is in the portal as well. Can you clarify how many monthly doses a patient in the Canadian U.K. cohorts can receive prior to going into the every 3-month maintenance regimen? Are they limited to only 4 monthly doses per protocol?

In general, assuming the patients have escalated, they would get 4 doses. Since all the patients are escalating, that means they didn't get 2 domains of plus 2 efficacy in the first 2 doses. If they did that, they would get only one more dose. Since all of them are escalating, they will all get 4 monthly doses, 2 at the lower dose, they should get 2 at the higher dose, and then they will transition into an every 3-month regimen. The next dose, the fifth dose they get will depend on whether they hit plus 2 during that period of time. If they did not hit plus 2 in 2 domains, then the fifth dose could step up from 5 to 7.5 and then we'll evaluate them again. And so that's how the dose escalation will continue even during the every 3-month period.

Okay. To work in a couple of non-Angelman questions here. I wanted to ask you about your Regeneron deal on Evkeeza. You talked a lot about what attracted you to it. How meaningful of a market might this be relatively speaking for Ultragenyx?

Well, it's around 3,000 to 5,000 patients in our area. For us as a rare disease company, that's a good number of patients, right? Depending on how many people actually get on therapy, you can imagine a pretty significant opportunity on what the pricing is. The pricing projected in Europe, we think, is around $300,000, but we don't think the pricing environment is where that is today. I think it's going to be tighter than that. In the U.S., the price for Evkeeza in the U.S. is $450,000. Now our expectation is going to be lower than the U.S. I'd want to guide people lower than to adjust just because I think European prices have been under more pressure. However, if there's 1,600 patients in Europe, a lot of them are being treated by apheresis, which is a horrible way to be treated because there's really nothing else. So if you can go to a once-a-month infusion instead of going on apheresis every week, right, sitting there for hours and hours. I just can see that as being transformative. When we did our key opinion leader work, we got glowing responses from people. This being the thing they want to use now for HoFH. So we think we could penetrate that market well. And even at a reasonable price point, I think we would see a substantial market. I don't know if you want to add anything to that, Mardi, about the market.

No. I think that covers it. Yes.

And then I know we're down to just a minute or 2 left. I wanted to ask on setrusumab. Just to be clear, the Phase II/III program, will you be providing an update on the Phase II portion later this year or is that just an internal one that's going to inform kind of how you take the Phase III forward?

Well, we expect to put out some information about that transition. How detailed it would be, I'm sure investors will be less satisfied since they want every little dotted I of information on every little thing. But we won't scratch that itch completely, but we'll put out information that we're perceiving that we've understood the dosing and some general information about it. But we have to protect the validity of the study and the integrity of the study as well. But we'll put out some information on it, Cory, but I'm sure it will never be enough.

It's never enough. All right. Listen, we're unfortunately out of time. Thank you guys very much for participating yet again, really appreciate it, good luck the rest of the week.

Thank you, Cory.

Thank you.