Great. Good afternoon, everybody. Thanks for joining us at the Bank of America Healthcare Conference. My name is Tazeen Ahmad. I'm one of the Senior SMID Biotech Analysts here at the bank. It's my pleasure to have our next presenting company, Ultragenyx, with us. Presenting this afternoon for Ultragenyx is Eric Crombez, who is Chief Medical Officer. Eric, good afternoon. Thanks for joining us here in Las Vegas.
Yeah, thank you.
So maybe we can start off with a quick overview of Ultragenyx. Maybe tell us about the platform of the company and some of the important catalysts that are upcoming, and then we can go into more detail.
Yep. Certainly founded as a rare disease company, and that is core to our mission. I don't see a straying from that anytime sooner or ever. But with the growth of the business, the growth of the pipeline over the many years, we've really kind of divided into therapeutic areas. The company was founded with Mepsevii, which is a lysosomal storage disorder and an ERT there. That really started the therapeutic area for inborn errors of metabolism, brought forward Dojolvi there, which has been an important treatment for fatty acid oxidation defects, and then really filled out that pipeline with the acquisition of Dimension Therapeutics, which brought me and our gene therapy pipeline into Ultragenyx 7 years ago. That's one of our next key catalysts with GSDIa with phase III data readout this quarter. So that's exciting and a long time coming.
Next therapeutic area was bone, certainly with Crysvita and the really great successful launch there, which continues to gain momentum and find patients. Also approved for TIO. Next following there from the pipeline perspective is setrusumab for osteogenesis imperfecta. We recently announced that we finished enrollment in the two phase III studies there. So that's an important data readout that could start as early as the end of year, beginning of next year, and then rounding out with our neurotherapeutic area. Certainly really important program with Angelman there, but with bringing in the program for Abeona, the gene therapy for Sanfilippo that's also in late stage, moving towards approval, and then really looking forward to our next IND probably likely being in CDD, which will be another central nervous system indication for gene therapy.
Okay. So maybe we can start in some detail with these programs that you've mentioned. I thought maybe we would start with OI today. Can you just remind us what the disease is and the standard of care right now and what you think or what Ultragenyx thinks the area of unmet need in that population might be?
Yeah. Osteogenesis. So I think historically referred to as brittle bone disease, which is helpful from a descriptive basis because that's exactly what it is. These children have a mutated gene leading to defective collagen, which prevents the laying down of really strong, dense bone. So these children really fracture very easily. We're looking at types one, three, and four because type two is so severe that it really is fatal prior to birth or right after birth. Some of these children, types threes and fours, will have fractures that are recorded as happening during sleep, meaning that just the tension of rolling over in bed or shifting is enough force to break bones in those children. So certainly a tremendous amount of unmet medical need. Some people in some region are using bisphosphonates. There has been a number of clinical trials using bisphosphonates in osteogenesis imperfecta.
Most of them had negative results. So certainly some improvement there, but tremendous unmet medical need left there.
When you think about bisphosphonates and the patients that are on it, is there a subset that you think are particularly amenable to your treatment?
Yeah. I mean, I think I guess if left with the choice between bisphosphonates or nothing, I think a lot of people are going to give bisphosphonates a shot. And really how people talk about it, and I think helps really understand what bisphosphonates can potentially do, it talks about locking in bone, locking in your calcium there, really trying to help prevent the turning over of bone that we see just with normal growth and no more day-to-day turnover. But we're seeing a lot of those patients coming into our trial who are continuing to fracture on at least an annualized basis. And certainly if you're having those types of fracture rates, I think it speaks to the unmet medical need.
With the data we put out last October, bringing that annualized fracture rate down to zero overall, that's a really significant improvement in fracture rate and very much supported by bone mineral density by DEXA there. So really seeing the increase in density of bone leading to reduction in fracture. So I think very much supports the data we're seeing there.
Yeah. On that data point that you presented earlier, it was six months' worth of data. And so I'm curious as to whether you think that's a good enough time period to be observing the effect of the drug on patients and what that durability could look like longer term?
Yeah. I mean, I think in some sense, I would say that it was really impressive results in that short period of time because what we're doing is trying to take out sclerostin. And sclerostin's job is to really maintain that balance between osteoblasts that build bone and osteoclasts that resorb bone. And by taking sclerostin out with this fully human antibody, we are able to really allow more osteoblasts to form and lay down new, stronger bone. So to be able to see that kind of reduction in fracture rate in a 6-month period of time is impressive. That's the point in time we were at. That gave us the ability to make the decision on dose, really confirm endpoints, and give us a go signal to the phase III part of Orbit.
In that sense, yes, you could argue it's early, but it was really compelling data, enough data for us to move to phase III.
Right. So before year-end, you are expecting to provide another update on OI. Can you just remind us what that is?
Yeah. So what we're looking at in Orbit is interesting because it was a phase II, III study. The benefit there was that allowed us to make the decision on dose and move seamlessly into phase III without stopping
for end of phase II and taking the time necessary to do that. So we have those original 24 patients that made up that data set. We released that data last October. Just by time on calendar, we're now looking at 6 months more of follow-up in all of those patients, giving you roughly a year in total. That will be the data update coming later this year.
Okay. If you think about the importance of this update relative to what you already showed us, where would you put that?
Well, I think that's exactly so. I think talking about time. I think it's really compelling data. It's 6 months. But you do want to see continue increases in bone mineral density. Certainly, we really want to get these patients towards normal bone mineral density. And we want to see that fracture rate, yes, coming down overall close to zero as possible, but on an individual basis, we want to see all these patients really coming down to a very low annualized fracture rate.
Whatever results you see later this year, would you still have flexibility if needed to make changes to what you're doing in phase III?
I mean, I think the easy answer would be yes, but that's an open-label study. So I do have a pretty good line of sight into what's going on in that trial. Everything is consistent. I'm not seeing anything that would change my mind on what's going on with those phase III trials. But again, with this type of disease that's driven by fractures, we're seeing that fracture rate come down. You're seeing the correlating bone mineral density. We have some biomarkers that also support this. It's a very tight, clear story with a very clear mechanism of action with this antibody.
Is there a mild, medium, and severe case of OI in terms of how patients are seen by doctors?
Yeah. So definitely type one patients are your least severe. You will, at the least severe end of the clinical spectrum, have patients who are probably rarely fracturing. But that still is really with a very modified, protected lifestyle. So these patients really limit what they do to prevent the type of trauma that could end up in a fracture. So I do think there's room for improvement there. But a typical type one patient who's coming into our trial is still fracturing on at least an annualized basis. But moving to threes and fours, those are the children who are in wheelchairs, need walk devices.
And that's one of those patients we talked about last October who was able to go from wheelchair to assisted walking device to playing on the playground to the point where his parents are like, "You can't pick him out of a crowd now." So your threes and fours, definitely the more severe end of that spectrum.
But you are trying to enroll everybody into the study?
Types 1, 3s, and 4s, we're not enrolling type 2s because it's so severe and fatal prior to birth or right around birth. They're just very severe.
Okay. And then just remind us how many diagnosed patients there are in the U.S.?
We really talk about 60,000 patients in the territories that we will commercialize in. I think we always say 20%-25% in the US. I had a phone up front.
Thanks, Josh. And then if we had to ask you how many of those patients you could find immediately, is there a way for you to find those patients easily?
Yeah. No. I mean, absolutely. Because this isn't the type of rare disease where patients go on a really long diagnostic odyssey that's hard to diagnose because these kids are really fracturing at a rapid rate. You're having these X-rays to support it. It's a very clear phenotype. So it's not hard. It's not difficult to work through that differential diagnosis. And I would think most pediatricians do understand this disease.
Okay. So then if we look forward to next milestones beyond the update that we've talked about for later this year, when do you think those are going to be?
Yeah. So we originally at the time because, again, Orbit is a phase II, III study. So we really were locking in and agreeing to that phase III part of that study before we had started phase II. And we had to design that study on the data we had available to us at that time. And that was the original study done by Mereo in adults and then really what we could collect through natural history and talking to people in the field. And then once we were able to collect that data in our phase III part of that trial, we realized that these younger patients, the patients we were enrolling, were fracturing at a much higher rate than adults. And then also with working with physicians in the patient community, really appreciating the underreporting of fractures, these parents will say, "We fracture so often.
We have all the splints, braces, casts, crutches to do what we need to do to manage fractures at home." So they know what type of trauma results in a fracture. And they're treating a lot of these at home and not spending all that time in ERs waiting for X-rays and stuff. So with the higher fracturing children and then taking into account the underreporting of fractures happening clinically, we were able to take a fresh look at the phase III part of that design.
That's really allowed us to look at that power calculation, realize we had really overpowered that trial, allowed us to come down in the number of patients we needed to enroll in phase III, and allowed us to introduce those 2 interim analyses we've been talking about with the first one with the potential to read out end of year, beginning of next year. Then we did put in a second interim analysis a few months after that as well.
To clarify, when you do take your first interim look at the data, will you only tell us if you're going to stop the study for overwhelming efficacy, meaning if early next year goes by and we don't hear anything, we're going to make the assumption that you're going to go for the full readout later?
Yeah. So it's not a date on the calendar that will trigger the interim analysis. I mean, if you think about it, we need the group of patients that were randomized, so setrusumab, to differentiate from those randomized to placebo. And it really is that fracture rate and the placebo arm and accumulating enough fractures to have success with the primary endpoint. So we do have an unblinded team that is walled off from the organization and really decision-making led by experts in OI. So they'll be looking at that data. And they only trigger communication to us as an organization if we achieve that primary endpoint. So we will know when there is success. And that's when, I guess, everyone else will find out as well soon thereafter.
Okay. So I think Emil has alluded to just make the assumption that we're going to go to the end of the study. What would good data at that time look like to you?
Yeah. So we originally designed the study to go through 18 months of follow-up for all patients. So it would be the last patient in up through 18 months. And again, I think we're really looking to see consistent results with what we saw at six months in that data firming up and holding true because with an overall the primary endpoint is annualized fracture rate, AFR. And with that coming down to zero, you can't do better than zero. So really looking to see that consistent reduction in fractures then, again, supported by that really significant improvement in bone mineral density.
Assuming that that's positive, you would file for approval. What type of infrastructure would you need to have that you don't currently have in order to market the drug because you do have Crysvita, which I think you market to the same physicians?
Exactly. And I think there's a real important synergy there. And that's why having these therapeutic areas and really focusing on bone within this group and having that experience with Crysvita and such good relationships with the community. And pretty much universally, all of the physicians who are using Crysvita also see patients with OI. And a lot of I mean, all of them really, I think, universally are excited about setrusumab because they always say they have a lot more OI patients in clinic than they do have patients with XLH. So I think so a really great infrastructure already in place and ready to go.
Okay. I guess one last question before we move on to the rest of the pipeline. What do you think is the part of setrusumab that makes doctors most excited?
I think this is one of those diseases. I think with all of the great work we've collectively done with rare disease, you don't have a lot of these types of diseases that really have true high unmet medical need. Yes, there's bisphosphonates. Yes, they help to some degree. These kids and adults are still fracturing. They're really trying to eliminate the amount of trauma that they're exposed to. They're really not leading full active lives. They're really just leading this protective life. It really ends up into a very sedentary, non-active life. I think if you can prevent these children and adults from fracturing and they can forget about this disease and go live their life, that's success.
Okay. So maybe let's talk about Wilson disease. We are expecting to see an update. I think it's scheduled for middle of this year.
Second half of the year.
Second half of the year. What data should we be expecting to see?
Yeah. So Wilson disease is great in a certain sense. Certainly, we have the pipeline where we've pulled through learnings for liver-directed gene therapy led by GSDIa and OTC. And Wilson is very much a liver-directed gene therapy. So a lot of understandings and learnings there. But the benefit with Wilson is it's a disorder of copper metabolism. And we can measure copper in the body in a lot of very different ways. And copper is meant to be loaded onto ceruloplasmin for trafficking through the body. With this genetic defect, you're not able to load copper onto ceruloplasmin, which means you have free copper, which is very damaging the body, leaking out.
So with the ability to measure copper in a lot of different ways, we'll think we'll have a very clear understanding of what's going on with the disease and give us the ability to select a dose and move on to the pivotal part of that seamless phase I, II, III study as well.
Yeah. So when you say seamless phase I, II, III , it's not something that I'm particularly familiar with. So maybe can you go into detail with what is it that is seamless about it versus doing a phase I and a phase II and a phase III?
Yeah. No. And it was a really great opportunity. And when we first designed this a number of years ago, the FDA was talking a lot about seamless phase I, II, III studies. And they were talking about it in the context of gene therapy. So we really decided to take them up on the offer. But it really does need to be the right disease because that means you're going from phase and oftentimes, we do combine phase I, II. You're not stopping for into phase II. You're not stopping to negotiate and get buy-in from the agency at that time. So you need to really have full agreement prior to going into clinic. And you need to understand what's going on. Wilson was appealing and a good opportunity for this because of the work that Alexion did on their next-generation chelator that they ultimately didn't bring forward.
But there was a lot of clinical regulatory precedents we could pull through and learn. So we felt like we understood the patient population. We understood the endpoints we need. And then you're just seamlessly going through. And that time saving for not needing to stop for into phase II, honestly, is at least a year and probably longer given the challenges that we've had coming out of COVID.
Okay. So similar question as before. As you go through these portions of the program, what are you considering to be good data?
Yeah. So we're calling it stage 1 because the nomenclature can get a little clumsy because that is the phase II part of it where we really are looking to make sure we do have the great endpoints and we're able to select a dose to take into what we're calling stage 2. And that'll be the pivotal part of it. So we're really looking at establishing the normal trafficking of copper by all these various methods to give us the ability to select a dose to go into stage 2, the pivotal part of that study.
Got it. How easy or difficult do you think it'll be to recruit patients?
So we have not had a problem recruiting patients at all, I would say, actually, compared to OTC and GSDIa where there is also quite a bit of unmet need. Recruitment for Wilson went very fast in stage 1. And that's really before you really have efficacy and safety data to speak to. So I think once we bring forward this next data set, that will be even more compelling and give people a lot of comfort to raise their hand and enroll in the phase III part of this.
Okay. How do you see the competitive landscape for Wilson?
Yeah. So Vivet's out there. They're also bringing forward a gene therapy program for Wilson disease. So we understand they're out there. Currently, patients are being treated with chelators and zinc. And they do help. But zinc just prevents copper absorption through the GI tract. And chelators are just pulling free copper out of circulation. So that means you need to wait for the hepatocytes to be sick enough or have enough damage that the free copper is leaking out in order to absorb it and pull it out of the body. So certainly, we think by providing a transgene that provides the fully functioning copy of this gene and establishing the normal trafficking of copper, it's got to be a better way to go.
What do you think, are patients underdiagnosed with Wilson?
So maybe to some degree, like all rare diseases are. But again, with the way this disorder presents, eventually, you are going to make your way through the differential diagnosis. It's not that rare of a rare disease where you're going to find pieces of the effect on the liver and elevated LFTs. You're going to find yourself to a GI doctor or a hepatologist. And they're going to understand this disease and be able to make the diagnosis.
Now, is there any synergy to be had with Wilson disease relative to the other indications that Ultragenyx has pursued, either in terms of doctors who treat the disease or other aspects that you think you can leverage from previous launches?
Yeah. No. It's absolutely an inborn error of metabolism. I was a practicing metabolic geneticist before I joined industry. And like a large number of OTC patients, GSDIa patients in clinic, I did follow Wilson patients as well. So certainly, you will have some overlap with our geneticists, metabolic geneticists. Some of these patients are also followed by GI doctors or hepatologists. But that very much will also overlap to some degree with the Dojolvi and the fatty acid oxidation defect. So in total, quite a bit of overlap.
Okay. Good to know. Let's talk about GSD. You've got an update coming there as well. Just remind us what data you think would be good there as well.
Yeah. So that's a traditional phase III that we'll read out this quarter. It is a double-blind placebo-controlled trial. So exciting for our gene therapy pipeline. It's, in a way, leading the way, I think, a little bit in competition with Sanfilippo syndrome that we brought in from Abeona. But we're really looking to, in a sense, replicate the results we saw in the phase II. We talk about the importance of cornstarch. And that's important because the FDA recognized that as a clinically meaningful endpoint, which means that if we were talking more about glucose or something else that'd be considered a biomarker, you're going down a surrogate likely to predict and committing yourself to a much longer, bigger follow-up study. So reduction in cornstarch as a primary endpoint gives us full approval. But I always kind of talk about speaking in full sentences.
It's that reduction in cornstarch while maintaining good glucose control. Because prior to the use of cornstarch, this disease was considered and was universally fatal. They just could not maintain glucose. They were ultimately always dying from a catastrophic episode of hypoglycemia, definitely much more vulnerable in the pediatric age range. So we want to see that reduction of cornstarch consistent with what we saw in the phase I, II, while they're also maintaining really good glucose control on that reduced or eliminated cornstarch.
So when you use the term cornstarch, it makes people think that this is a simple solution. And you're exploring a complex treatment option, gene therapy. And so for people who may be on the fence about what the market opportunity is, can you explain to us why Ultragenyx is excited about it?
Yeah. No. That was definitely kind of a shift in thinking for me too because I had treated these types of patients in clinic. And I knew how fragile they were. And they're really dependent on this cornstarch for life, not because they had to take it every day for lifelong. But in some cases, particularly in pediatric patients, if you miss a dose, you can really have a life-threatening episode of hypoglycemia. So cornstarch is really just, in its raw form, sitting in your GI tract and being very slowly metabolized, so providing some level of glucose. But they're still taking it every 2, 3, 4, at most, 6 hours. So you're waking at least once during the night to do this. And it's very burdensome. And they're still having episodes of hypoglycemia. They're not doing as well as they could.
We're not just looking at the cost of cornstarch and the reduction there, but really the total burden to the healthcare system. They still are ending up in the hospital sometimes in an intensive care unit because of how severe this metabolic derangement can be and just really looking at that totality of effect there.
So assuming you have positive data, what's your timetable to apply for approval? And in terms of manufacturing, where are you on it?
Yeah. So I think manufacturing, you could argue, is probably on a critical path now because we were trying to partner with contract manufacturing organizations. There were challenges that I think a lot of people are having. We had just built and opened that brand new facility just outside of the Boston-Cambridge area in Bedford. So we thought, "Now, wait. Why not bring this into our manufacturing facility, have control, have confidence in what we're doing to support that launch?" We're still working through the specifics of that timeline but looking to file as quickly as we possibly can.
For infrastructure that would be needed here, how is the company thinking about that?
Yeah. No. This is absolutely inborn errors of metabolism. It's core to what we do. It's your geneticist. It's your metabolic geneticist. If some of them ended up again in a GI or hepatologist's office somewhere around the world, we have coverage there as well.
Okay. Let's talk about OTC, which is the other gene therapy program. Where are you on that? I know you're further behind on this one than you are in GSD.
Yeah. Because the pipeline has been so big and I'm going to hit soon my 7-year anniversary at Ultragenyx. And in that 7-year tenure, we have not had anything fall out of the pipeline. So that means everything has been maturing and pulling through. And we have a lot in late stage now. So we made the decision to prioritize on GSDIa. We really doubled down on getting that enrolled and supporting this. And then so, to a degree, a little bit de-emphasizing enrollment of OTC. But once GSD was fully enrolled and on track, we've now shifted our focus to OTC and looking to complete enrollment in that phase III trial this year.
Okay. And then what is the unmet need for OTC?
Yeah. So kind of in a descriptive sense, there's alternate pathway therapy available for this. And with the urea cycle, you're not able to metabolize ammonia that comes from protein. And ammonia is a very potent neurotoxin. So really looking to establish normal flux through that cycle and ammonia and sorry, totally lost track of your question.
Oh, the unmet need.
Oh, yeah. So these patients still on alternate pathway therapy are still going to have what we refer to as metabolic crises where, whether it's inflammation for a viral disease or they're taking in too much protein from their diet, they'll have these really rapid increases in ammonia, again, a very potent neurotoxin. They can quickly go into coma and die and always accumulating irreversible neurologic damage, which each episode of these metabolic crises is.
So if you were to compare, I don't know if we should, GSDIa to OTC as you describe it, this seems to be more dangerous for patients left untreated.
So yeah. It's a difficult comparison because both of them do have a mortality rate associated with them. Both of them are episodic in the fact that you're fine until you're not. I think OTC is a little bit different. With GSDIa, you always need to be maintaining a normal glucose level. With OTC, with current existing therapy, you're fine until you have something that's triggering great metabolic demand. And then you're really at risk of going into that metabolic crisis. So different but also a lot of similarities.
Okay. Then before we close, I did want to touch upon that other program, Angelman. I just wanted to ask whether or not Ultragenyx has had its end-of-phase II meeting in detail with the FDA and what the next steps are?
Yeah. So end-of-phase II meeting is on the calendar. So that'll be the next big step. That is what was so important about that data readout that we just released. That will be the basis of our briefing book. That will be the basis of that conversation. But again, we've been talking about the ongoing conversations with the FDA, really to make sure we're tracking in the right direction, that we're directionally going towards agreement and really de-risking that end-of-phase II because our plan is to come out of that with agreement and get that study started and getting our first patient in by end of year.
Is there any concern from Ultragenyx about using an endpoint for phase III that wasn't necessarily the preferred endpoint when you were looking at the program initially?
So we're going to bring forward cognition by Bayley as a primary endpoint. And we have been looking at that very closely. So we are very comfortable with it. I think when you look at just the domains we've been talking about, cognition, speech, gross motor behavior, and sleep, those are the important domains. I think where the conversation could be had is, "What type of assessment do you use to evaluate that?" But again, directionally, we've been having these conversations. They're very familiar with what we're doing. And we know the FDA is comfortable and understands the Bayley.
And then the last question is one that I get a lot from investors, which is the competitive landscape. Biogen and Ionis presumably have their own data update sometime this summer. Is there anything to the view that you could have competing end-of-phase II meetings with the FDA? And FDA would only really want to pick one endpoint for a pivotal study no matter what the company is.
Yeah. So again, we do have the data on the calendar for our end-of-phase II. Again, in the conversation we've had, they haven't been signaling that they're pushing us in a direction that we don't want to go in or something that doesn't make sense to us. And we're not seeing any signal that Ionis is leading there necessarily. I think it is fair to say that the FDA does like to have the ability to compare similar mechanisms of actions in similar diseases. So I think as a guiding, they do like to do that. But I think from what I can tell, I think we're leading here.
Okay. Perfect. With that, we're out of time. Thanks, everybody, for joining us this afternoon. Really appreciate it. Thanks so much, Eric, for coming out here to Vegas to talk to me.
Yes. Great. Thank you.