Analyst at Jefferies. It's with great pleasure that I'd like to welcome our guest today, Emil Kakkis, the President and CEO of Ultragenyx. Thanks so much for joining us, Emil. This is gonna be a fireside chat format. Maybe to start off, for those who are new to the story, if you can provide a one-minute intro to Ultragenyx.
Sure, happy to do that. Happy to be here in London again. Christmas already beginning.
Yes.
So Ultragenyx, founded in 2010, we've been in business, 13 years. We're a commercial company focused on rare diseases. We have four approved products generating $420-$450 million revenue this year, and we have 5 late-stage programs, phase III programs, and phase II programs that are, you know, a variety of indications. We've recently put out data at our Analyst Day on the three larger indications, the Angelman program, which I'm sure we'll get into in detail, an antisense oligonucleotide that is increasing the developmental function of patients with Angelman syndrome. Another late-stage program now in phase III, for osteogenesis imperfecta, showing a profound 67% reduction in fracture frequency and potentially transformative drug for osteogenesis imperfecta.
Finally, we actually put out the first bit of data on our Wilson Disease gene therapy, showing that they are metabolizing copper coming off their chelators in that disease and showing improvement in copper distribution, which we think could be a superior way to treat Wilson Disease from the current chelators. With those programs coming forward, we think as we look forward for the company, we see our burn decreasing further, heading toward profitability in 2026. And we are, you know, I think, at a really important inflection point as a company in terms of having a commercial global base, as well as a rich, probably the richest rare late-stage pipeline. And I think, on our view of everything right now, that everything is working, and so I think we're in a very unique place to transform the future of rare disease medicine.
Got it. Yeah, I think that's a great intro, and, for commercial, you recently reiterated guidance for $325 million-$340 million on your third quarter call. Looks like you're assuming that Crysvita is gonna have a strong fourth quarter, and you've mentioned uptake in Latin America. Maybe talk a little bit about what metrics you're tracking in this region that gives you confidence.
Yeah, so Crysvita continues to do well. It crossed $1 billion in global revenue last year, and the U.S. launch start forms increase are faster than they were last year. We have more people in the field since we're supporting Kirin and ourselves, both in the field in the U.S. And while the revenue numbers are always a bit lumpy for it, and there's always a bigger fourth quarter, we... We reiterated our guidance for the U.S. It continues to grow steadily. It's now primarily commercialized, driven by the work of our partner, Kirin, although we managed it fully for the first five years. We're still in the field working with them in promoting the product, and we'll continue to do so because of the importance.
Latin America, for Crysvita, we are continuing and will always be the commercial party, and it's really picked up well. In fact, the start from growth is similar to what the start from growth was last year in the U.S. You know, we crossed 500 patients on commercial drug in Latin America now, so it's becoming a significant contributor, and we own a bigger fraction of the P&L in Latin America compared to the U.S. So one Latin American script is kind of worth like two U.S. scripts in terms of value to us, right? So it's important to us in our growth. We're also getting some traction in Turkey finally.
It's taken a little while, but we do—we were given the Turkey, and we have other products in Turkey, is why it's become a country of importance for us. They have a lot of metabolic disease in Turkey. So those are the factors, I think... I think Crysvita still has ways to go in penetration. You know, we have, you know, depending on how you calculate it, 40% of the pediatric patients, but maybe 15% of adults. There's still room to go, and we're continuing to find patients, and when we do, the probability of getting on drug is very high, and people stay on the drug. Once they get on it, they feel better. It changes their lives, and, and so it continues to grow with a very good persistence rate.
I think it's a program, I think, to continue to grow, and I think continue to grow at the 20% a year kind of rate for a while. So, we're excited about Crysvita in the long term, and it's an important part of our future.
Got it. And for Dojolvi, how is that going with education efforts needed for LC-FAOD and getting patients to optimize doses there?
Right.
How strong has demand been, and how much of the market have you penetrated?
Right
S o far for this program?
Well, for Dojolvi, it's treatment for a long-chain fatty acid oxidation disorder. They have terrible problems with their muscles and liver and so forth. They end up in the hospital a lot, and this is... so it's a horrible disease. But we've crossed 500 people on drug in the United States, and more than 150 now in Europe on named patient sales. And we're tracking with a very strong, beating expectations on start forms. The challenge that you referred to is that some of the doctors are using the dosing closer to what they used to do with MCT oil rather than the dose we prefer. We've provided some training material to help people understand the difference and why they should titrate up to get the maximum effect, and that's having some impact.
We're seeing an improving dose titration going on for patients. But the uptake has been impressive, and one of the things with that product is once a doctor tries and puts a patient on to see how they do, then they start adding. We just need to get those doctors to do their first scripts and get going, and once that happens, it grows. The European named patient work in France started with a couple doctors treating five or six patients about four years ago, and it rapidly turned into 30 doctors treating 100 patients in France, just through word of mouth. Once the patient got treated, they saw how they did, they started adding more. So we think it's a really valuable product. It has an important contributor to us because its margins are excellent for us.
We continue to drive the program forward globally. South America is slower. We've been focusing on Crysvita, but it will pick up, and we're looking at how to get it in Japan, and Japan being a new territory for us, where we have Evkeeza from Regeneron as well as Dojolvi and our other programs.
Got it. And so looking ahead to 2024, what are specific programs, markets, or market dynamics where investors should be focused, and where you think there's potential room for upside?
Well, I think the big picture for us is you can't ignore Crysvita in the US and its continued growth, 'cause it's a big piece of the total story. But the big highlights of improving action, I think, are Latin America Crysvita and that continued growth there. I think the growth of Dojolvi globally, I think will be an important piece. And Evkeeza, although small, is now in launch mode in Europe and Canada, and will start in Japan next year as well. Expect to get approval in the first part of the year and launch in Japan.
In all those territories, we have a high level of KOL interest, a high demand for compassionate use, and Evkeeza is really the most potent reducer of cholesterol of any approved product, and that 50%-70% reduction in cholesterol is on top of everything they're on. 50% was from the trials, but that's on top of everything, still a further 50%, so it's very potent. If you look in the most severe patients that have the more pure genetic versions, they have to have 70% reduction. So we think it's something that will become widely used in the very severe population of HoFH. While it's narrow and it's not a huge product, it will be, I think, picking up and going next year, so it'll start adding to our top-line revenue.
Got it. And, let's shift gears to Angelman syndrome. At your recent Analyst Day, you showed encouraging longer-term Angelman data there, and you've guided to dose expansion data in the first half 2024. In the update you mentioned, we should see ASA, Bayley-IV, and MDRI data from 10 patients with longer data, and then 20 patients with six months data, and 30 patients worth of data of any type. Maybe talk about what you wanna see in the first look at patients from the expansion cohorts and what a home run scenario could look like.
So the majority of that will be about the 20 patients that have at least day 170. The 10 patients will have day 254 worth of data. The day 170, we should be able to see the benefit of the load. So those. The patients, the data we just disclosed were titration patients that started at lower doses and titrated up. And the data we showed then was, I think, excellent improvement in Bayley cognition, Bayley gross motor, and receptive communication, and we showed improvement on the Angelman severity assessment for sleep and behavior. And we'll focus on those domains again in this next data set, which will primarily be driven by the 20 patients that have day 170. But we added those other elements, and we'll show you other parts of the data.
So our expectation is that we should be able to show equal or better results in the same time frames that we saw, because the dose, the average loading dose, will be higher, and the maintenance dose will go more directly to the maintenance dose, whereas in the other data, we were titrating up maintenance over time. The other study was about figuring out dose, and this time we're testing the dose that we would expect in phase III. So I think you'll see what we saw before, but perhaps I think we would expect higher levels of improvement than we saw before. I think we will see many of the same emerging skills that you saw, that we mentioned before in the emerging skills analysis. And what we will do is show how we would analyze this for phase III.
By that point in time, we'll have had some discussions with FDA about endpoints, and we can provide more color on the endpoint choice, although the final decisions on the endpoints for our phase III program will depend on an end of phase II meeting. But we have scheduled a meeting with FDA either late this year or early next year. We'll have a meeting with them to talk about the endpoints for phase III. We have a lot of choices in front of us. We'll focus mostly on quantitative endpoints, and the MDRI, or Multi-Domain Responder Index, is a way to analyze five endpoints together for clinical meaningfulness. It's, I think, a more effective way to look at the totality of the data, and we showed that analysis, the analyst data, to show you how powerful it was.
'Cause you could see across five domains how many patients had boxes that turned green, meaning they were positive. It just gave you a sense of the breadth of changes in all the patients. It tells you something of why this is transformative. It's not just one here, one there. It's many patients have three or more domains of clinically meaningful improvement. We think we also showed you video data and other types of data to help provide more color. And I think what you could see, for example, we talked about gross motor improvement. It's a little different when you see the couple of the kids walking. You can see how wide-based their gaits were and how narrow they are, how comfortable they are. If you imagine those changes happening in all these different domains at the same time, the same patients, it's, it's an amazing result.
The FAST meeting was exciting. A lot of parents coming up to me who were in the trial or doctors who are seeing patients, and, you know, there's a growing buzz of how there's a possibility here with, with Angelman to really change their future. So, that's what you'll hopefully see at that time. The end of phase II would happen after our next disclosure and would be a place where we'd finalize endpoints, and our goal would be to get that done as promptly as we can so we can head to phase III, which we'll set, start setting up in the second half.
Got it. And for that meeting with FDA by end of this year or beginning of next year, what type of meeting is that, and would you do some sort of an update after you get the minutes from that meeting?
Yeah, it's what they call a Type C meeting. The FDA told us at the last meeting we had that they were open to having it, and they've agreed, and we've actually set up the meeting. So it's not an expected meeting on the normal milestone set of meetings. So it's an extra meeting, and they're willing to have it 'cause they know how important it is. I don't know that we'll provide an update. It depends. We'll provide an update that we've had it in progress, but it's likely going to start the discussion about what we're gonna work on, and the main thing for us is to learn from FDA, what do you need in the final package to get comfortable, right? Because what happens sometimes, if you make that first discussion into phase two, then you spend several months chasing down stuff they want.
So by doing it earlier with the data in hand, it'll give us a chance to chase down all those bits and pieces to make sure, because there are so many endpoints, because they're first ever in a disease, our team, we have a whole team at the company, a very special thing in our company. This is an endpoint development team that actually focus on endpoint development. It'll give them a chance to lay out what do they have to do, so we come back with a fulsome package and get agreement promptly with FDA when we have the full data. So we'll have enough data to talk with them, so they'll see what it looks like, and, and we'll provide an update on, well, on our progress, but I wouldn't necessarily expect final decision on endpoints until we get to into phase 2.
Got it. Makes sense. And you haven't disclosed the exact doses you're using for cohorts A and B in the expansion. When are you going to disclose more information on dosing?
Well, because it's a competitive program, we've decided to be a little more reticent to give all the information. What we have said during maintenance dosing, that we're dosing between 10 and 14 milligrams, so that should allow you to calibrate to some degree. The other companies haven't said what they were dosing at, but they are dosing at much higher doses than that. The dose loading is lower than the original cohorts 4 and 5, and they will be loading through. Cohorts A and B are loading 4 of those doses and then titrating into the 10 to 14 range quickly. So, it will be, let's say, within day 170 timeframe that we're showing you data, they will have had more drug on board than what we just showed you. Okay? So the exposure should be higher.
So far, we've treated 30-plus kids, and we're doing well. We're not having no significant safety issues. We're doing well.
Got it. And you mentioned the FAST meeting, which was pretty recent, and Biogen Ionis also had the first update there from their clinical study. It was a pretty high-level update, but what are your perspective on what they reported, and yeah, anything new there that's interesting?
They reported very vague data in the sense that they said that a majority of patients had some improvement in their EEG and improvement in wave frequency on the EEG, but didn't say what improvement that was, how much, but just that it had some, which meant it could have been a little bit. And then they had some improvement, some fraction of patients had an improvement in Bayley, but not how much. The problem with the Bayley is that up and down 2 or 3 points is kind of like within the noise, so you kind of really need to know if you're crossing thresholds. Since they knew what our data was, since we presented ours at Analyst Day several weeks before, they certainly had the opportunity to show what they had. They didn't.
My guess, based on their design, that they probably couldn't beat what we have right now. But I think it does say that their drug works, that there's an activity. So I think just like Roche's, I think, was working, but I think their efficacy is not as great as ours is, and I think the main reason for that is a targeted region whereas we have, and it's patented, it's far more potent, manyfold more potent than the other regions. So that's why we think we have a particular scientific edge that they won't be able to overcome.
Got it. Makes sense. And at your Analyst Day, you also showed EEG data that looked very good. How important are these data to certain key Angelman investigators as it relates to enrolling patients in your studies? And how could this factor into a pivotal study? How does FDA view this factor?
Yeah. Well, I think the EEG data was more important to investors, actually. At least that's who really was interested in it. Because they wanted to see something objective, because people think that maybe the Bayley scores change without objective— But actually, the Bayley scores are very hard to change in open label. I've done a lot of studies. They rarely move at all. So when you see movement in Bayley, it's hard to get, I guarantee you. But the EEG just tells you that there's an underlying biological mechanism ongoing, that you're actually changing brainwaves. It tells you there's something fundamental happening, and we showed statistically significant reduction in, in 1-4 Hz delta waves, you know. That shows you their brains are starting to speed up in how they're signaling, right?
The waves is essentially a measure of neuronal communication, that they're actually speeding up, that there's less of the really slow, high-amplitude waves. So it then we showed how it correlated with cognitive. Their cognitive scores improved in a proportion how their delta wave. It shows you that we're changing brain function in a fundamental way that's predicting very significant improvements in cognition. From the parents' perspective, and what the doctors listen to, is what the parents tell them, which is: "My kid is a kid, is actually a kid now. Actually, my kid's awake and alert. My kid is... lights are turned on. He can follow instructions, one or two-step instructions." Usually, they don't, they don't even recognize their name nor language. So you talk to the kid, they don't hear anything. They don't understand. It's just gobbly to them.
And now they start being able to hear language and understand, "Oh, that's my name. You want me to look at you or, or stop doing something." So when parents tell the doctors this, what happens is, when they're seeing it, they're sending the doctors videos of what the kids can do. And so that's what's contributing to the excitement among the doctors. They're seeing stuff that they, you just don't see. And honestly, in the history of drug development and rare or anything, how many times have we even taken someone with severe developmental delay and actually start improving normal function? R ight? In multiple domains of function, right? This is something very special. So there's no question about enrollment. We have no issue about enrollment, more about people upset we don't have sites in every country where everyone is.
So I had everyone buttonholing me on, "Come to Poland, come to Argentina, come to wherever." We are trying to cover as many countries as possible, but, you know, right now, we gotta make sure we get a phase II completed and hit phase III on path. But, I think the buzz is very positive, and I think people wanna be part of it, and that's what's driving the enrollment. Patients are lined up. The bigger problem is too many patients that wanna get enrolled. So now, this is for an intrathecal therapy, and there's no doubt that's pretty invasive. But if you've ever known anyone or had a kid that was developmentally delayed, and they start doing stuff they couldn't do before, like start feeding themselves, potty trained, some of them hadn't been potty trained, they were potty trained.
Walking without falling, you know, not pulling the hair of their siblings or at daycare. These, if you add that up, all happen at the same time, you know, it's a change of life for these families, so there is a huge drive to do this.
Yeah. Makes sense, and my last question on Angelman, just if you can talk about your understanding of the total data that you have and the natural history data. What's the optimal amount of time that you need to treat patients in order to see efficacy? And then talk about what a registrational study could look like in that context.
Yeah, well, we showed for all the endpoints, kind of a growing separation between the two lines, and day 254 kinda looked like the really good spot in terms of the maximum change, and the EEG change really became more maximal at 250 compared to day 170. So, I mean, day 254 seems like a place where the separation is greatest. You have to imagine this is intrathecal, and we're doing a double-blind, placebo-controlled trial. How many placebo injections do you want to put kids through, right? When you tell a family you're gonna enroll in the study, how long is that gonna be?
We think eight months is, I think, close to the limit where we would see the effect we wanna see and to try to limit the number of placebo injections a kid, you know, a kid with developmental delay has to take without any benefit. So that's where I think day 170 is possible, but it's a little shorter. So between those two, somewhere in there is the right spot, I think. I think regulatory authorities will always want longer 'cause they have no idea what people go through and what it's like. So I just think doing too many placebo injections don't make sense, and fundamentally, I'd rather enroll more patients and have a little bit shorter study and get done to give them the comfort.
And the other thing I would say is, once you prove that the groups have separated on a placebo-controlled trial, you've proven the cause and effect of the drug. You can still continue to follow those patients in open label to say: Is it still progressing? 'Cause you've proven this effect is the drug, and then it's possible to continue to follow that effect and not have to reprove it at every stage. So the other question is on safety. I think eight months is long enough in safety to have enough injections to be able to show what, what it looks like and what happens, with regard to all the lab tests and everything else, right? So I think there's enough time. Our expectation is to have 100 to 120 patients in that range.
It's, let's say, 8 months. It would be randomized, placebo-controlled, not sham. Placebo, because I think doing sham opens the door to things being discovered and not perfect and not Type I evidence. And if you have a transformative therapy, the last thing you wanna do is deal with an HTA somewhere saying, "Well, that study is not really the right design. We're gonna give you a lower Z-score." And I just think doing one high-quality, fully randomized study is the way to go with something that's important and then large as this one.
Makes sense. Moving on to setrusumab, maybe talk about the fracture rate data that you showed there recently, which was impressive. How's the phase III enrollment going, and what are you hearing from investigators?
Yeah, so one of the osteogenesis imperfecta is a defect of collagen, and as a medical geneticist, I was trained like everyone else, that that defective collagen made weak bone. But no one ever really proved that exactly was true. And when you actually test the physical strength of the bone, it's not really the collagen is not making it that much weaker. The truth is, and this is very important about these results, is that what's happening in OI is that there's bone dysregulation. They're not making enough bone. The Z-score of bone mineral density is two standard deviations below normal, right? So they're all the average is the fifth percentile.
So the trouble is they don't make enough bone, and what we saw in the animal models, if you normalize bone mineral density, just normal, the bone strength on a fracture test was normal. That's kind of mind-blowing, even though the collagen's still mutated, right? So this is like a change of mindset. So most people didn't realize if we just make more bone, that bone will be strong, and these patients will stop fracturing. What that data finally allowed us to show, to jaw-dropping surprise for all the people, experts in the field, is that you could have kids stop fracturing and have a 67%, 20 out of 24 didn't have a, a clinically meaningful fracture. Only four did, and half the fractures, four, were in the first three months, right?
So after, there was only a few fractures a little bit later, and no one after 7 months had a fracture in the study. There were people there for a while. One kid with Type IV was 17 months on study, has not had a fracture in a year and used to be wheelchair-bound, now is running around, is, is not in a wheelchair anymore. That was a case we showed, and also has had falls that, as Karen said, would definitely should have caused fractures, but no fractures. So that's kind of a mind-blowing idea, that maybe we can strengthen their bones, and we don't have to fix the collagen, which is gonna be very hard to do. And what we showed is a 67% reduction in the fracture frequency, but that's including-... even from the beginning of the treatment period, right?
If you imagine now watching them longer when the fracture rate goes way down as their bones get strong, and if you're a pediatric patient, we showed a 19% increase in bone mineral density in the pediatric age group in six months, right? Just a fundamental change in their bones. It's like their bones have been waiting for someone to turn them on, and we finally touch them, and their bones just start making bone, and the fractures go away. I'm so I'm really excited about the potential. The high reduction rate tells you something's really profound going on, and I think that setrusumab for osteogenesis imperfecta could be a transformative therapy for these kids, and we're excited about that because I think it's... You don't have to fix the collagen to actually fix their bone problem.
Yeah, makes sense. And for the phase III study, you've talked about interims for the study and potentially downsizing it, too. What proportion of the 195 patients would be needed to conduct the interim analysis? And talk about some of the-
Right.
The other triggers in the study.
The original assumption was that the patients had 0.67 fractures a year and a 50% reduction treatment effect size. The true fracture rate is probably much higher than that because that's based on reported to the doctor, and we found out the patients don't report most of their fractures. Whereas in the study, we're gonna everything will get reported, right? So that number, even if you look at the data, we would go up to 0.7 or point 0.75, just a little bit higher fracture rate and the higher reduction rate. The study is then much overpowered. So we originally powered it to be 85% power to detect a 50% reduction with a 0.67 baseline.
So right now, we haven't said exactly, but let's say we think that the trial could roll between 150 and 195, somewhere in there, could be more than enough with the power estimate we have now. I think the true effect size could be higher than 67%, but with that assumption, and I think with the true fracture rate being found, I think that we'll have more than enough power with a smaller study. And the interims we'll do will be based on when they get to a certain number of fractures, a certain amount of time to get to a certain number of fractures. And we won't announce the interims unless we stop the study, and the DMC will be running that unblinded interims. We have the FDA acceptance, but I think we're gonna have very strict result.
P-value needs to be really small, so there'd be no question ethically you really couldn't continue the study. And those interims won't cost anything on power 'cause it'll be small enough p-value change, you won't have to pay an alpha fee for that. So we'll do two interims and then the final, and that will hopefully give us a chance of ending the study early if the effect is what we think it is.
Got it. Makes sense, and I think we're pretty much, almost out of time, and we haven't talked about a couple important programs from your gene therapy, pipeline. Maybe highlight, some of the key points for those programs and the events ahead that investors-
Sure.
S hould be focused on.
Wilson program, gene therapy, we presented some really intriguing data of patients coming off their chelators from the first cohort at the lowest dose, which we were surprised how well they were doing, and the fact that their copper distribution going up, which means that the gene therapy is functioning even at the lowest dose. So we will, in the first half of next year, show you data from the second cohort, which is already dosed, and the third cohort, which is being dosed now, which will give us data through these 15 patients sometime in the first half. Give us a chance to see what the right dose is for phase III and then trigger the initiation of phase III. So that data will be important.
If we continue to see and the patients seem to feel really good, physically well, my hope is to be able to show with these data that there's a benefit to improving copper distribution, not just copper detoxification, which I've always said these patients have both deficiency as well as toxicity at the same time. And if we can show that, it could be that the Wilson upside is much higher, greater. The MPS IIIA program for Sanfilippo is a very urgent indication. We are talking to FDA. We have all the patients treated that we plan to treat. We're just trying to negotiate the timing of filing, whether they wanna wait for a certain level of clinical data, or can we file for an accelerated path using the biomarker data. But that's moving along. We're getting the CMC part straight.
We were essentially tossed that program from Abeona. It was working. I felt the responsibility to not let it drop because I think it's a gene therapy for a terrible disease segment. I've been personally involved in four out of five approved MPS therapies, but I haven't done a Sanfilippo, so we're gonna do this one and not let it go. So those two, and then we have OTC. GSD I will unblind the first half of the year. That's for glycogen storage disease. It's, b y the way, in gene therapy, urgency is what matters. Glycogen storage disease patients are living every day taking starch every few hours with a gun to their head, they're gonna die if they miss. And people ask: Why would some gene therapies launch well and some don't? It has to do with the urgency. These people want to be in the study.
They want to get off this treadmill they've been running on, this you know, everyday thing about dying, if I don't take my starch thing. It's a crazy way to live. The parents are stressed out, too. So that program has urgency, and I think if that's successful, I think people will want that gene therapy, just like MPS III, where they're gonna... It's like SMA. If they don't get treated in the first couple of years, they're gonna die, and parents know it. So those are a couple where I think there's a high urgency. That's why I feel commercially, I think they will be successful if they get through. So that's a lot of, a lot of phase III programs all at once.
We've built our own plant, and we have a complete gene therapy program, and I think we're doing the right things to bring the cost into line as a company, get our burn down, and we're projecting continued decreases in burn. That means we did put some programs that were early stage, two INDs on hold. They're waiting, and one program, GSD III mRNA, that we paused because we just couldn't invest in everything to manage the burn efficiently. We restructured some R&D groups, tightened up, and then put the heads in the clinical development area that we need for the phase III and the high priority programs. So with those disciplined actions, our burn came down this year a lot from last year. It will come down further next year.
We said 2026, we expect to get, you know, in the range of being profitable and mostly driven off the 4 commercial products we have, but the beginning launches of some other programs at that time. I think we're at a really important inflection point as a company, having commercial product growth, multiple products in late stage, and a team that knows how to do it. If we look at the 2013, 2014 IPO class, how many people have 4 approvals in that timeframe, right? What we showed is our data on one slide. Look how many products we're gonna have, we think approved 8-12 in our first 15 years of company. That tells you that the team knows how to develop things, get approved.