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

Great. Good afternoon, everyone. I'm Salveen Richter, biotechnology analyst at Goldman Sachs. And we're really pleased to have Emil Kakkis, Founder, President and CEO of Ultragenyx.

So Emil, it's been quite a few years since you founded this company; and you've emerged as a commercial story with a pipeline that continues to evolve. Just to level set, as you sit here today and you look at the commercial aspect and the pipeline and the modalities you brought in, where do you see kind of the future of Ultragenyx going?

Well, first of all, I'm very happy, at 12 years, to be a commercial company with 4 approved products; to have 5 late-stage programs, which is hard to do; and then to be heading into $420 million, $450 million revenue this year. [ So an ] important turning corner as we start to head toward profitability of the company, we're managing our OpEx to manage this level that we're doing right now. And our expectation: As revenue continues to grow at a 23% rate, we will head toward profitability going forward. The question is how do we build the company. And in 2016, '17, we had -- a lot of our programs have made it through approval and we were in this situation of how do we set up for this next period. And one of the things that's clear to us is we need to have some bigger wins along with some other traditional rare and ultrarare, though we couldn't have all ultrarares. And so as part of that, we started building out the pipeline with some additional larger programs; and those programs are starting to bear fruit. So one, we just announced data on osteogenesis imperfecta, which is program we think that will be as large or larger than Crysvita. Crysvita globally -- though we don't own the whole of it, but it globally passed $1 billion last year in global revenues. I think setrusumab for osteogenesis imperfecta will -- I think, will equal or exceed that, [ for sure ]. And this time, we own the majority of the value. That was one of the programs we brought in with the deal with Mereo. Second, we added the Angelman program, which of course many people are excited about and interested in. And we're excited about the possibility of improving the development of children with developmental delay. It is something that's been elusive and maybe thought to be beyond our ability, but the [ science you're ] suggesting in this disease is you can do it. That's another very large opportunity for us. So in addition to that, we have a group of gene therapy programs that are entering Phase III. And that becomes another place where we can add a lot of value with a gene therapy type portfolio. We've built our own manufacturing plant. Part of that story is to manage the cost and cost structure because gene therapy can't be just a USD 3 million price point. I think that's not going to stand for all -- so many diseases, so we have -- with our Pinnacle PCL platform, have worked on managing costs and COGS to set up for a price point that might be lower than what people think but still have it be an appropriate margin for a business that can grow. And by setting up our own plant, it brings our costs down further, so it lines up, to have a gene therapy, to be a commercial, feasible and potentially transformative direction for us. We'll continue to be mode agnostic, but we don't want to develop platforms ourselves in general. Our use is to -- we try to use platforms rather than develop them. And I think we are looking at neurology and metabolic neurology as areas of still a lot of need, as metabolic bone genetic disorders are still. There are many more disorders to work on there [ and then more areas ] we've certainly done a lot of work. I think we're going to stick in those 3 areas primarily going forward, mode agnostic, but we're looking at having a mixed risk-return with some bigger opportunities middle sized and small ones. And that's part of our philosophy of optimizing the risk-return so we can maintain a steady growth rate going forward. If you look at what we have in front of us with even any average success rate going forward, we will have as many products approved as rare disease companies [ as practically any ] in history, including a company where I was at, BioMarin. So I think our productivity has been exceptional. We need to continue that as well.

Jumping into the portfolio. You talked about Angelman's, and we're going to see some data later this year. Can you just remind us of the metrics that will be considered here or that we should focus on? Which patients we will see data on the details as it relates to dose level and follow-up and then how we should evaluate that in the context of what we've seen.

Sure, sure. It's a more complicated study now because the Phase II has several arms. And so -- and the categories of data that we're accumulating are 3 different work streams of data. The first was the long-term extension of the patients treated in the early cohorts, dose escalation cohorts, last year that are continuing on treatment. 13 of those are past a year. Some are 1.5 years from treatment. We've shown time and dose-dependent improvements in their function, and we feel very good about long-term safety now. So that's there. And that will be some additional data that we would potentially put forth. Second is the original 5 patients. 3 of them re-dosed and are collecting data. And now with the opening of the U.S., we were able to dose the other 2 again, who were anxiously waiting to get dosed again. So the re-dosing of those patients has another -- it's a small set of data, but it allows you to calibrate what we saw before, right, at the other dose. And now it's a new dose, a new regimen. I think that will be important in kind of aligning thinking about what we're seeing because those will be the same patients treated both ways. The third cohort is what we're doing right now, which is the expansion cohorts. Once we kind of figured out what the dose range should be, we established then we needed to treat 40-some patients at that dose. And the point was to get enough patients to really have a volume of data to give you confidence when we're looking at various developmental function improvements. That program, which we had started ex U.S., there were 8 countries involved. And the sites are getting set up and they're operating and enrolling. We now add the U.S. to it to -- a set of cohorts in the U.S. as well. That will give us a set of cohorts that would take us probably to more like 50 patients total or in that range. And that allow us to show what are the dose level, common dose level, load look like and maintenance in a certain range. And it will give us a body of data that might give you kind of a sense for what Phase III would look like. From that, we'll also get narrowed in on what you should be looking for in terms of efficacy. We focused in on 5 or 6 domains and we're looking at multiple end points in those domains. We will come together -- later in the year, we'll talk with the FDA on the clinical outcome group, COA. And then we'll also talk with the FDA about end point choices later in the year, but we're trying to look through these 5 or 6 domains and come up with the best plan. We think a multi-domain plan makes sense because different patients respond differently and have different problems, but it could be we pick one domain as the primary and we have the others as secondary. So we'll work that through. We've been focusing a lot on quantitative measures like the Bayley score for expressive or receptive communication, but we're also looking at things like an Angelman severity scale or assessment, which is a new score created, for particular domains like sleep. We're looking at other end points as well, like the Vineland or a behavior scale to deal with maladaptive behavior or other particular fine motor skills and growth motor skills, so we'll have a grouping of end points. And we'll probably narrow it down to the -- what I would call the key end point for each domain, and that's the [ kind of operation ] we've put out. What do we see? What do we think are the key domain end points that we would use and what we're discussing with FDA? So that's a lot of complexity there. The disease is complicated, but what I would say to you is that, in the history of I've been working on this, I've not seen a treatment that would improve cognitive function; improve expressive or receptive communication; improve basic fine motor skills like using fork; or gross motor, tripping, falling, instability problems; or maladaptive behaviors; or sleep. Sleep is one -- some people don't think it's that important, but if you're a parent and your kid doesn't sleep, it's extremely important. And I would say that one alone is probably enough for most parents to want to do it. And patient 5 from [ the first program ] was one of those kids that never sleeps and [ some 6 year-olds ] that doesn't sleep at night. I'm sure -- you have kids, so you know not sleeping at night -- like for 5 years. When he got drugged, he started sleeping through the night. And the parents -- it was transformative for their lives, right? And then when he got pulled off drug because of a safety event, it was absolutely demoralizing. I got this -- and after all the time it took, she sent me a note, just horrified with how life has changed for them again. We were able to get him started and he started sleeping again, and it was just exciting. Within the -- like one dose, he -- within 2 weeks, he started sleeping again. And he's been sleeping again since he started again, so she wrote a nice note to the FDA reviewer who agreed to treat her kid, so she could get some good feedback. I think that was probably helpful, but when you talk about [ clinical inputs ]: We're seeing things that are really transformative for families. Now if you imagine -- throw in that sleeping problem; and then understanding commands now, receptive communication; or being able to use a device to communicate where they hadn't; or saying first words. You combine that in the same kid. It's a big change. It's a big change of live, so I feel like we're in a very exciting place. And I feel the fact that we have chronic long-term safety data. We have 3 ways of collecting that information. And we'll come out later in the year with releases, but I expect that. Plus, in the first part of next year, there will be more patients treated [ with more ]. We want to get enough data, at least 6 months of data, in the expansion cohorts; and enough patients to be a definitive release, so we'll look at that. I wish the U.S. had opened a little earlier. It -- but it's opened, so we're excited about getting this thing really moving ahead like it needed to.

You've talked about a multi-domain end point, so when we see this data set by year-end, will we have an understanding of these different domains? Like could we see data on all of them?

Yes. We'll have what the domains are. The domains that I can tell you are communication; sleep; behavior; fine motor; gross motor; and probably the sixth one, cognitive function. So those are the domains. And the question is what's the best end point for each. The Bayley on cognitive function is well accepted. And on expressive or receptive communication, it's probably good, but on some of the others, it's not as good because the patients are starting at a very -- way down the scale, all right, so they don't do as much as what the Bayley is looking for. And so in some of those situations, you need to use a different scale that's more appropriate with where those kids are starting. So we will talk about what domains end points we have and what we're choosing. I'll throw in there the CGI scores. The CGI scores are certainly a reasonable way to do a primary end point, but they're not quantitative. They're somewhat subjective. And so there is more complexity at interpreting them, but the value of them is they've very sensitive. That's why people use them. They're very sensitive to change, so -- however, even if we use CGI as the primary, like a CGI Angelman as primary, you still would want the quantitative data in the secondaries to kind of substantiate the clinical meaningfulness of what that score means.

Do you think we'll be able to interpret this data when we see it just from the context of not -- given the natural history and not having a control arm? Like how do we understand what that variability means or doesn't mean?

That will be my job. If I fail to make it good, I'll understand what was in that one. That was probably what happened to us last time. I don't think we did a good job of putting the context. So when we do the data, we'll do it 2 different ways. 1 way will be comparing it to natural history control data and try to do a propensity score type where you actually match exactly, but we'll have a natural history control so you could see, for that end point, what does it look like. What I can say to you, because I've been looking at it, the natural history control is basically flat for everything. There's really no movement. Like it's minuscule, so -- but we will have that control data. And then the second question is, okay, you can show relative natural history, but is this amount of change clinically meaningful? What does that mean? So we'll want to have a second step of calibrating clinical meaning from this. Whether it's using minimally important difference scores or some other clinical end point on clinical meaningfulness, we'll make sure to have that second part for each end point.

Great. On the safety side, do you feel like that's relatively been dealt with where you have a decent profile now based on the dose work? And was it really all dose work that was driving it, or do you think there was an aspect to the construct itself?

Well, the construct or the structure is -- so it's a gapmer with a locked nucleic acid, LNA, structure, which are definitely drugs that can be more -- have more toxicity. So that's known, but it's also way more potent, like orders of magnitude more potent. So the truth is that, the value of the LNAs, you can have very high potency. And since we're talking about doses in the range of, let's say, 5 to 14 milligrams, I'm talking about a very potent ASO compared to others which are 10- to 20-fold higher doses, right? So it's a very potent molecule. What's key is that we are not letting the molecule stick locally. What we -- I think, we're going on is that the ASO, when administered, especially [ when the kid is set up ] quickly after the [ LP ] -- the drug was settling in to this -- the nerve there and just loading up locally. And that was causing the inflammation, irritation. By simply doing Trendelenburg [ and ] the flush step, which is easily done, it keeps the drug from being too concentrated and sticking or adhering locally. And we've shown in monkeys, we did this work in parallel that -- in monkeys, that doing Trendelenburg [ and ] flush in the monkeys -- comparable equivalent in the monkey gives us several-fold higher brain levels of drugs without really changes in lower back so much, but it just changes the brain a lot, which tells you you're probably saturating uptake locally. And if you just move the drug up, you actually get more in the brain so that the same dose level might be giving you several fold more equivalent efficacy, if that makes sense. So it looks to us like several-fold better. It was actually quite surprising. I would say most of the nonclinical people looking at it were surprised how big a difference it was. So I do think that change allows us to get the efficacy we need without having to increase the dose.

So if the profile looks good on this data update, what are next steps? And with the FDA, do you have a sense of what they may allow for the regulatory update? Are they in line with you on this multi-domain situation? Or where are they coming at this?

Well, I think in our meeting -- by the way, we did talk a little bit with FDA about the next steps. They do want us to go see the clinical outcome group. And then they agreed that they can meet with us later in the year about end points. And they understand the complexity. So once we've met with them, we can go to them and talk to -- and they'll meet with us to talk about the end points. We didn't go through the multi-domain responder-type approach at this point. The FDA has shown some interest in it; and some, not. It's still tricky. It will be something that will take some work, I'm sure; at least maybe show them an update on how it would play out. Because I think they're conserved. They don't like being surprised. What I would say to you, Salveen, is even if we pick a primary end point of some type, we can put the multi-domain responder analysis as a secondary end point right there and still get the same benefit to us, as long as we pick one that's going to win and then pick another one that gives us another way of looking at multiple domains across the patients, so I have no doubt we can figure out a way. I think the fact they're interested -- we discussed the design of the randomized, placebo-controlled trial. And they were agreeing to that, so with the -- that's important because, before, they were more concerned about placebo. And I really think, if you're going to do this type of end point, you need to do one high-quality placebo-controlled trial to end the discussion for all time whether this is real or not, right? It's very real. It's very transformative, but you've got to do one study that takes that issue off the table. So they've -- they're supportive of that, and that's good. And our hope here would be -- before doing the other indications, we're doing the deletion of this program, as we would do the other ones through open-label supportive studies rather than doing multiple rounds of randomized trials.

Setrusumab you talked about that as a $1 billion-plus sales opportunity here. And we saw some Phase II data recently in young and adolescent patients, so help us understand, when we look at the P1NP and bone mineral density data sets, how that reads through to your Phase III primary end point, fractures, and really on a clinical benefit standpoint.

Sure. I think one of the -- we read data on P1NP and BMD which were extraordinary, I think. I mean -- or mind blowing because to achieve what was a year's worth of bone mineral density improvement in just 3 months was really something, and particularly also the Z-score improvement of 0.65-plus. The mean at baseline was minus 2 [ in factor ], so that means 1/3 of the bone mineral density deficit is already recovered in 3 months. It just tells you how potent this mechanism is for these patients. And given how poor their bone mineral density is, it's not so surprising, Salveen, that the bone mineral density is really low, that improving is going to strengthen their bones. So they're very low. They're as low as minus 4 Z-score, but the average is minus 2, so that much movement up, I think, is very substantial, so the question is does BMD improvement predict fracture improvement. And I know a lot of people have found inference maybe it does or it doesn't, but it's very important to ignore, like, random association. So it's very important to look at BMD changed by an agent rather than just correlation, so if you just take a bunch of people and say, "What's their BMD? What's their fracture frequency?" you'll find noise, right? The key question is taking someone that has particular bone mineral density and improve them to a certain amount. Would their fractures improve? With regard to that, there is a difference between antiresorptive and anabolic agents. And I think, if you separate them out and look at the data, you will find that the anabolic agents will predict that increase in bone mineral density by anabolic, producing new bone, will correlate with fractures, whereas antiresorptive is more mixed. And that's where a lot of confusion is. So this mechanism of setrusumab is making more bone. It will lay down bone where it's weakest because the way bone cells get targeted is they are targeted wherever the bone structures are wiggling and moving. And it's actually a [ piece of ] electric signaling system. If anyone is interested in biology: It's amazing. Your body can tell when the fibers are moving, so when you're pounding by walking, they're wiggling a little bit. That wiggling causes the surface of these cells -- if they're wiggling and moving, it says, "Oh, I'm weaker because I'm moving." They will actually change their surface. And they'll attract bone cells to land there and start making bone, so your bone is microfine laying down bone cells where they need to be. That's how you create this network of structure that looks like an engineer diagram. How do the cells know where to be? They know because of the signaling mechanism. That's how they know where to land. So all we're doing with sclerostin is we're dialing up anabolism, but where the cells do, they do what they're supposed to do. They land where the bone is weak and they start making bone there. That's why we think the structure will improve. We didn't put out fracture data yet, but what we did say, the investigators were really pleased and excited about improvement of bone health, which meant fractures in patients in that -- how bones feel and then how patients were being. So they're very positive with what they're seeing. We have patients who have been on drug at least a year now; some, 6 months; some, a few months, right, so there's a range, but their sense is that this is going to be transformative for these kids. And that's Dr. [indiscernible] it's quoted on, but -- so we feel very comfortable that this is going to predict, but I think it's important to understand the biology and understand why this is different from antiresorptives. Bisphosphonates only have a 20% decrease in fractures because blocking bone and keeping it where it does, does not put bone where it needs to be, right? It's a fundamental error. It is not the right way. It is one way that someone figured out that helps bone mineral density, but it doesn't solve the problem in OI, so I think it's really important to understand that difference. So when we look at that data, I look at we're in great shape and I feel that this will be transformative. So we're very encouraged. And our main thing now is looking at how to conduct the study and enroll it promptly, how to construct the interim to determine if we can end sooner. And these data give us more encouragement that the efficacy is very fast, and therefore, we might be able to end the trial with the last patient and not spanning a long time but maybe a year or potentially less.

Could you speak to the dose work that's been done here? So when you decided to move forward with the 20 mg per kg versus 40 mg per kg, was there any dose-limiting toxicity or anything with the 40 mg per kg that you saw throughout your work here? And what if the minimal benefits that we're seeing at 1 and 3 months kind of widen as you go beyond that period?

Yes, it makes sense for people to worry about that, but when that widened before, like, between 8 and 20 during the ASTEROID study, there was a big difference in P1NP between those two. It wasn't small. There was a big difference. So let's explain things: What P1NP is, it's a snapshot of how many bone was made in the last year or 2. What BMD is, is accumulation of how much bone has been made in the last month. Does that make sense? One is a snapshot. One is accumulation. So if the accumulation -- if the acute snapshot is really not different, all right, it's very hard to get to a lot more bone being made. The truth is -- on the BMD at 3 months is that there was even smaller difference than it was on the [ aim ], right? The difference in BMD accumulation was even smaller. We look at all of the details of it. There just wasn't a reason to go to 40. The 20 was giving us such a rapid effect. It was near maximal. And in general our -- in principle is we don't like to push the dose of something. It creates an unknown. We know the dose safety of 20 for a year. We don't know what 40 would do. And 20 was much simpler. We tested 40 for one reason only, to try to exclude something profound happening. We didn't want to miss that. It wasn't. Could we use higher doses sometimes? It's somewhere in the program. I think it could be, but I think 20 is a very good nominal dose. I feel like the probability that you're going to see that differential is low. So we've been looking at all of the data throughout that we have. I don't think there is enough of a difference to make it worth it. There's -- one way to think about this also is, once you saturate the antigen, the antibody, giving a lot more antibody doesn't necessarily make things go better, all right, once the antigen is fully saturated, right? This is a pretty high-dose antibody, 20 mg per kilo, 40 mg, so it's also mechanistically not that hard to imagine that you've kind of saturated sclerostin already. And therefore, pushing it a little higher -- it might be different in 1 or 2 -- in some patients, but it won't be optimal. Now in the long run, if we were dosing everyone double what they needed and we launched, which means that everyone could cut the dose in half and still get the same effect, well, it would be [ being ] a lot more product that you didn't need to. It wouldn't make much sense, so I think we're very secure on the choice. We don't think you're going to see enough of a differential [ in matter ].

And then could you speak to the differentiation versus rosomozab (sic) [ romosozumab ]?

Yes. So romo is -- or Evenity is a drug that signals through the same epitope, close to it. It works in terms of [ acting in ] the same system. The difference with Evenity is it's safe. It's humanized, not fully human. When you're talking about chronic dosing settings -- because they're doing 1 year and that's it, all right, for each patient. When you're talking about chronic dosing for years, like all of life, then the immunological issues are more and more important than being fully human. It's very positive. We don't have any hypersensitivity reactions in the trial, so -- and I think that safety piece in chronic administration is a differentiator. I think the other thing is that we're dose optimizing. And dose regimen, it's going to be more than a year. We've -- from the ASTEROID data, when they stopped the patients, even with bisphosphonates onboard, they had some declining bone density. They started losing bone density within 2, 3 months, so it was pretty clear OI is not the same as osteoporosis from this regard, right, that the signal for breaking down bone is stronger than for osteoporotic patients. So that means you need chronic dosing, so we will have chronic dosing in our label. That would be a differentiator. Instead of 1 year in bisphosphonates, we would have a chronic regimen. I think that will be another factor. I think ultimately, commercially, we're going to be taking care of our rare disease patients the way we always do, with home care. 85% of Crysvita is administered at home actually, not in the hospital's clinic, even with an IV infusion. We do that for Mepsevii. It's our enzyme therapy. So we'll deliver this in a way that's convenient and support patients with co-pays and that support and everything else that we would do that would be normal for our care. So I think those are -- all said, I think there's biologic and other regimens that are different, but fundamentally I think that Amgen is not interested in OI. They gave us a license. We're on [ a nonexclusive ] license on the epitope, which would not have happened, I think, if they're really interested in pursuing the indication. And so I think that kind of tells us it's not their direction. And -- but keep in mind, if you have an osteoporosis drug, safety is really key. If you have to put all of the safety events from osteogenesis imperfecta in your label, right, it's not simple, right? Very complicated. So I feel like both can coexist. In the end, we're going to have to look at how we price, all right? How is pricing? But I think there is a way for us to be priced in a way that allows us to gain the majority of the value without creating a strong impetus for off-label use.

As we look to your gene therapy portfolio, we're going to get 2 data sets in the first half of next year. So GSDI as well as Wilson's. Could you just put into context for us what we should see and whether that would be basically proof of concept here?

Yes. So the GSDI study, fully enrolled, enrolled very quickly. We've had a lot of interest in that program, which kind of tells you how serious the disease is. Because people were kind of saying, "It's not that bad. You're just taking starch." It's serious. It's scary for people. It's like living with a gun to your head. So we enrolled very quickly. And what we'll be showing people is what -- cornstarch reduction is the primary end point; just showing that they can -- instead of needing constant oral glucose infusion, that they'll -- they can now rely on their liver to start maintaining their glucose, which is freedom and safety, right? It's freedom. You don't have to carry starch with you wherever you go. It's freedom from having to worry about exercising and doing anything causing you to go hypoglycemic and freedom from thinking you have to wake up at night or you might die. So that's what cornstarch reduction clinically means. FDA, at first, was unsure about it because it seems too trivial. And then they did a listening session on it and then they agreed then, so -- well, which we had done it too, but they convince themselves on their own, which is good because that means they're actually listening to what patients are telling them. So that's the primary end point. We'll have some other scores and functional scores and other aspects of how they're doing, their tightness of control. We have continuous glucose monitors on them, which will help tell us what they look like at night and how their body is behaving. So that will be the prime thing, cornstarch reduction, glucose control and how patients feel and function in that setting. It's a randomized, placebo-controlled trial, one of the first in gene therapy. There's not many, right? The Wilson program is in the dose stage and the data that will come out will be the dosing information. We have 3 dose levels, which are basically 5e12, [ e13 ] and 2e13. 5e12 was very low. We were asked to do this because of FDA's concern about safety, although I don't think it was a long-term viable dose, but basically we'll have 5 patients per cohort. And we'll look at both urinary copper, serum copper and ceruloplasmin. In that situation, we're looking for are we controlling copper and urinary copper. Have we lowered it? The idea being that, if the liver is pumping copper into the bile system, then it won't be dumping it or free to be dumped out into the urine, right? You -- when you chelate, you don't find it because it's already been pumped out. The ceruloplasmin is very important, though. If the transfer is working, it should be putting copper into the Golgi as well, which is where it will -- copper will get loaded on ceruloplasmin. Ceruloplasmin is the copper carrier that deliver into the body. And it's very important to realize that Wilson patients' total serum copper is actually low, not high. It's low because ceruloplasmin is low. So the body's mechanism for delivering copper is gone. What's high is free copper, but the free copper is a very small number, right? It's really important. So the truth is we worry about the free copper, but the truth is the bigger problem is they're not delivering copper the way it used to be. And you know the body doesn't do things for fun, just for games; put copper on ceruloplasmin and send it around your body when you don't need it. You know that, that is core, So we've all gotten used to just saying, "Hey, chelation is all you need," because we didn't have anything. This is the first time or a chance for us to show you can get copper back on ceruloplasmin and normalize copper distribution. And what I believe is going to happen, you're going to see neurological problems that you -- that aren't resolved by chelators that will get resolved here because they're actually copper deficiency -- that all Wilson patients have copper deficiency overlaying copper excess at the same time. We know this is probably true now because there are some patients with severe neurological problems despite chelation who will get resolved by getting a liver transplant. See that's your test. You get a liver transplant and you get normal ceruloplasmin. Suddenly your neurological problems get better, right? So I think the understanding of Wilson is going to change by virtue of treating it. And if that's true, it will change the whole paradigm thinking; that chelation will be a partial fix, not a correct fix. And so gene therapy could become a more dominant way of dealing with it. And fortunately, for that program, we have the Pinnacle PCL platform. We have a new plant, and the platform has greatly reduced our cost of goods. And so for an indication that large, it puts us in a position of having incredible commercial thesis for how you might do this. And so we're really looking forward to the Wilson data and getting to the end, but that will be the Phase II data and then we enroll a Phase III study after that. The recent termination of the Alexion-AZ program kind of highlighted this mechanistic thing, right, because they have these mechanistic studies that didn't explain what was happening because the problem with chelation is not the issue. [ Inactive chelation ] is not really the problem. The problem is copper distribution. And I think they were able to figure that out and so they pulled away. And that was the only real competition, I think, going on for us from other treatments, so I think that opened the door to understanding why gene therapy may be the way.

Great. Any questions from the audience in the last minute? I think we're good...

There's someone waving back there.

There is a question over there.

[ Is that ]...

We saw [ in your last CPS set ] [indiscernible] multiple ascending dose [ version ] for UX053 and just wondering how you're thinking about resource allocation. I know that you have multiple late-stage programs. And what you look for in your discussion [ on what to ] prioritize.

Yes. So the glycogen storage disease. The mRNA-LNP program was the one that kind of had to be held because we just had to manage our burn and it was the most costly and earlier-stage clinical program. We decided to put the resources and funds into OI and Angelman acceleration. And when we stopped is -- we had a single ascending dose data. We stopped there. We enrolled patients and filled out that part. And then we're doing some work on the CMC and scaling. We all know that mRNA is someone figured out how to make it for vaccine globally, but for mRNA treatment like this, we still have a little bit more work to do. But our hope is to come back to it, but at this point, we'd have to get in a financial situation. We couldn't do everything, so we had to pick; picked OI and Angelman as top priorities, gene therapy ones that were advanced in Phase III that we would keep going. And then we removed some spending there. And we held off on a number of INDs, including Duchenne got held a little bit and some other ones that we didn't put forward. So the truth is we've got a tremendous number of pipeline opportunities in front of us, but we've got to manage the spend. So look at the net cash OpEx -- net cash burn from OpEx to be under $400 million this year. We're just trying to clarify what happened last year involved a lot of onetime things; as well as, before, we did some small amounts of restructuring and prioritization to tighten up the operation, but we're in a good shape now, I think. And each year, our burn should be going down. We will keep our OpEx tight, our head count; and just let our revenue grow and take us to profitability.

Great. Well, with that, Emil, thank you so much. We appreciate it.

Thank you.